U.S. patent number 6,266,560 [Application Number 09/336,400] was granted by the patent office on 2001-07-24 for electrically assisted transdermal method and apparatus for the treatment of erectile dysfunction.
This patent grant is currently assigned to Genetronics, Inc.. Invention is credited to Gunter A. Hofmann, Dietmar Rabussay, Lei Zhang.
United States Patent |
6,266,560 |
Zhang , et al. |
July 24, 2001 |
Electrically assisted transdermal method and apparatus for the
treatment of erectile dysfunction
Abstract
A non-invasive method is provided for treating erectile
dysfunction using electroporation enhanced with delivery of a
vasoactive or androgenic composition applied to the penis which
affords an alternative treatment for patients afflicted with
erectile dysfunction (ED). Sufficient electric pulses temporarily
create new pathways in the penile skin thereby driving a
composition, such as a vasoactive or androgenic medication, into
the corporal cavernosum.
Inventors: |
Zhang; Lei (San Diego, CA),
Hofmann; Gunter A. (San Diego, CA), Rabussay; Dietmar
(Solana Beach, CA) |
Assignee: |
Genetronics, Inc. (San Diego,
CA)
|
Family
ID: |
22219988 |
Appl.
No.: |
09/336,400 |
Filed: |
June 18, 1999 |
Current U.S.
Class: |
604/20;
977/906 |
Current CPC
Class: |
A61N
1/36007 (20130101); Y10S 977/906 (20130101) |
Current International
Class: |
A61N
1/36 (20060101); A61N 001/44 () |
Field of
Search: |
;607/39,43,20 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
Primary Examiner: Kamm; William E.
Attorney, Agent or Firm: Gray Cary Ware & Freidenrich
LLP Haile; Lisa A.
Parent Case Text
This application claims benefit of provisional application Ser. No.
60/089,869 filed Jun. 19, 1998.
Claims
What is claimed is:
1. A method for enhancing erectile function in a subject, said
method comprising applying an electric pulse to the penis and
substantially contemporaneously applying a vasoactive or androgenic
composition thereto, said electric pulse having sufficient strength
and duration for transdermally introducing an effective amount of
the composition into the penis, thereby enhancing erectile function
in the subject.
2. The method of claim 1, wherein the electric pulse is applied to
the penile glans.
3. The method of claim 1, wherein the electric pulse is applied to
the penile shaft.
4. The method of claim 1, wherein the electric pulse has a voltage
from about 50 to 80 volts.
5. The method of claim 1, wherein multiple electric pulses are
applied.
6. The method of claim 1, further comprising restricting venous
flow from the penis.
7. The method of claim 1, further comprising iontophoresis.
8. The method of claim 1, further comprising vibration.
9. The method of claim 1, further comprising administering a
vasoactive or androgenic composition to the subject orally, by
injection or transurethrally.
10. The method of claim 1, wherein said composition is a vasoactive
composition selected from the group consisting of prazosin,
PGE.sub.1, PGE.sub.2, PGE.sub.1, papeverine, PGA.sub.1, PGB.sub.1,
PGF.sub.1, 19-hydroxy-PGA.sub.1, 19-hydroxy-PGB.sub.1, PGE.sub.2,
PGA.sub.2, PGB.sub.2, 19-hydroxy-PGA.sub.2, 19-hydroxy-PGB.sub.2,
PGE.sub.3, PGF.sub.3, PGI.sub.1, PGI.sub.2, carboprost
tromethamine, dinoprost tromethamine, dinoprostone, lipoprost,
gemeprost, metenoprost, sulprostone, tiaprost, nitroglycerin,
isosorbide dinitrate, erythrityl tetranitrate, amyl nitrate, sodium
nitroprusside, molsidomine,
(Z)-1-{N-methyl-N-[6-(N-methyl-ammoniohexyl)amino]}diazen-1-ium-1,2-diolat
e (MAHMA/NO),
(Z)-1-[N-(3-ammoniopropyl)-N-(n-propyl)amino]diazen-1-ium-1,2-diolate
(PAPA/NO),
(Z)-1-{N-[3-aminopropyl]-N-[4-(3-aminopropylammonio)butyl]-amino}diazen-1-
ium-1,2-diolate (SPER/NO), sodium
(Z)-1-(N,N-diethylamino)diazenium-1,2-diolate (DEA/NO), linsidomine
(SIN-1), S-nitrosothiols, S-nitroso-N-acetyl-D,L-penicillamine
(SNAP), S-nitroso-N-cysteine and S-nitroso-N-glutathione (SNO-GLU),
smooth muscle relaxants, leukotriene inhibitors, calcium channel
blockers, .alpha.1-adrenergic antagonists, .alpha.2-adrenergic
agonists, phosphodiesterase inhibitors, antihypertensive agents,
angiotensin-converting enzyme (ACE) inhibitors, angiotensin II
receptor antagonists, phenoxybenzamine, dibenamine, doxazosin,
terazosin, phentolamine, tolazoline, prazosin, trimazosin,
alfuzosin, indoramin, ergotamine analogs, ergotamine analogs,
acetergamine, brazergoline, bromerguride, cianergoline,
delorgotrile, disulergine, ergonovine maleate, ergotamine tartrate,
etisulergine, lergotrile, lysergide, mesulergine, metergoline,
metergotamine, nicergoline, pergolide, propisergide, proterguride,
terguride, diazoxide, hydralazine and minoxidil, nimodepine,
pinacidil, cyclandelate, dipyridamole, isoxsuprine, chlorpromazine,
haloperidol, yohimbine, trazodone, apomorphine, bromocriptine,
naltrexone and vasoactive intestinal peptide.
11. The method of claim 1, wherein said composition is an
androgenic composition selected from the group consisting of:
androsterone, testosterone, dihydrotestosterone,
dehydroepiandrosterone (DHEA), DHEA sulfate, enanthate, propionate,
cypionate esters of testosterone, phenylacetate esters of
testosterone, testosterone alkyls, methyltestosterone,
testolactone, oxymetholone and fluoxymesterone.
12. A method for treating impotence in a subject comprising
applying an electric pulse to the penis of the subject and
substantially contemporaneously applying a vasoactive or androgenic
composition thereto, said electric pulse having sufficient strength
and duration for transdermally introducing an effective amount of
the composition into the penis thereby enhancing erectile function
in the subject.
13. The method of claim 12, wherein the electric pulse is applied
to the penile glans.
14. The method of claim 12, wherein the electric pulse is applied
to the penile shaft.
15. The method of claim 12, wherein the electric pulse has a
voltage from about 50 to 80 volts.
16. The method of claim 12, wherein multiple electric pulses are
applied.
17. The method of claim 12, further comprising restricting venous
flow from the penis.
18. The method of claim 12, further comprising iontophoresis.
19. The method of claim 12, further comprising vibration.
20. The method of claim 12, further comprising administering a
vasoactive or androgenic composition to the subject orally, by
injection or transurethrally.
21. The method of claim 12, wherein said composition is a
vasoactive composition selected from the group consisting of
prazosin, PGE.sub.1, PGE.sub.2, PGE.sub.1, papeverine, PGA.sub.1,
PGB.sub.1, PGF.sub.1, 19-hydroxy-PGA.sub.1, 19-hydroxy-PGB.sub.1,
PGE.sub.2, PGA.sub.2, PGB.sub.2, 19-hydroxy-PGA.sub.2,
19-hydroxy-PGB.sub.2, PGE.sub.3, PGF.sub.3, PGI.sub.1, PGI.sub.2,
carboprost tromethamine, dinoprost tromethamine, dinoprostone,
lipoprost, gemeprost, metenoprost, sulprostone, tiaprost,
nitroglycerin, isosorbide dinitrate, erythirityl tetranitrate, amyl
nitrate, sodium nitroprusside, molsidomine,
(Z)-1-{N-methyl-N-[6-(N-methyl-ammoniohexyl)amino]}diazen-1-ium-1,2-diolat
e (MAHMA/NO),
(Z)-1-[N-(3-ammoniopropyl)-N-(n-propyl)amino]diazen-1-ium-1,2-diolate
(PAPA/NO),
(Z)-1-{N-[3-aminopropyl]-N-[4-(3-aminopropylammonio)butyl]amino}-diazen-1-
ium-1,2-diolate (SPER/NO), sodium
(Z)-1-(N,N-diethylamino)diazenium-1,2-diolate (DEA/NO), linsidomine
(SIN-1), S-nitrosothiols, S-nitroso-N-acetyl-D,L-penicillamine
(SNAP), S-nitroso-N-cysteine and S-nitroso-N-glutathione (SNO-GLU),
smooth muscle relaxants, leukotriene inhibitors, calcium channel
blockers, .alpha.1-adrenergic antagonists, .alpha.2-adrenergic
agonists, phosphodiesterase inhibitors, antihypertensive agents,
angiotensin-converting enzyme (ACE) inhibitors, angiotensin II
receptor antagonists, phenoxybenzamine, dibenamine, doxazosin,
terazosin, phentolamine, tolazoline, prazosin, trimazosin,
alfuzosin, indoramin, ergotamine analogs, ergotamine analogs,
acetergamine, brazergoline, bromerguride, cianergoline,
delorgotrile, disulergine, ergonovine maleate, ergotamine tartrate,
etisulergine, lergotrile, lysergide, mesulergine, metergoline,
metergotamine, nicergoline, pergolide, propisergide, proterguride,
terguride, diazoxide, hydralazine and minoxidil, nimodepine,
pinacidil, cyclandelate, dipyridamole, isoxsuprine, chlorpromazine,
haloperidol, yohimbine, trazodone, apomorphine, bromocriptine,
naltrexone and vasoactive intestinal peptide.
22. The method of claim 12, wherein said composition is an
androgenic composition selected from the group consisting of:
androsterone, testosterone, dihydrotestosterone,
dehydroepiandrosterone (DHEA), DHEA sulfate, enanthate, propionate,
cypionate esters of testosterone, phenylacetate esters of
testosterone, testosterone alkyls, methyltestosterone,
testolactone, oxymetholone and fluoxymesterone.
23. A method for delivering a composition into the penis of a
subject comprising applying an electric pulse to the penis and
substantially contemporaneously applying the composition to the
penis, said electric pulse having sufficient strength and duration
for transdermally introducing the composition into the penis in an
amount greater than provided by passive diffusion of the
composition into the penis when applied thereto.
Description
FIELD OF THE INVENTION
The present invention relates generally to erectile function, and
more specifically to methods and an apparatus for treatment of
erectile dysfunction.
BACKGROUND OF THE INVENTION
Penile erection depends on the relaxation of cavernosal smooth
muscle. Relaxation of the trabecular smooth muscle permits dilation
of the lacunar spaces, causing engorgement of the penis. Inflow of
blood at the systemic blood pressure to the lacunar spaces expands
the relaxed trabeculae against the tunica albuginea. This
compresses the subtunical venules, reduces venous outflow from the
lacunar space, and elevates lacunar space pressure, making the
penis rigid. Contraction of the cavernosal smooth muscle leads to
penile detumescence. This results in a reduction of arterial inflow
and a collapse of the lacunar spaces with decompression of
subtunical venules and increased venous outflow from the lacunar
spaces, returning the penis to the flaccid state.
Penile erectile dysfunction is a common medical disorder. It has
been estimated that it is prevalent in 2% of men aged 40 years,
which an increase to over 50% in men over the age of 70 years,
affecting some 10 to 20 million men in the US alone.
Intracavernosal injection of vasodilators, such as prostaglandin E1
(PGE1, alprostadil; CAVERJECT.TM./Upjohn-for intracavernosal use),
is a commonly used treatment for erectile dysfunction (Porst, J.
Urol. 155(1996)802-812). When injected into the penis,
prostaglandin E1 can induce an erection within a few minutes in up
to 80% of cases, and acts by relaxing the smooth muscle of the
penis. Different formulations of prostaglandin E1 are now available
and have been compared (Vanderschueren et al., J. Urol. 154(1995)
1744-1747). Mechanism and side effects have been studied (Granata
et al., Psychosom. Med. 57 (1995) 336-344; Italiano et al.,
Pharmacol. Res. 31 (1995) 313-317). Although effective, the
drawbacks of intracavernosal injection therapy include the
inconvenience of injection, discomfort, stress and pain during
injection and penile scarring (Gana et al., Curr. Ther. Res. 57
(1996) 700-710; Chen et al., J. Urol. 155 (1996) 138-140). As
prostaglandins undergo first pass metabolism and adverse reactions
such as diarrhea follow oral use, they cannot be administered
orally.
Other methods for treating erectile dysfunction include malleable
(bendable) or inflatable penile implants or prostheses, which are
manufactured by several different companies. However, such devices
require surgery. The use of penile suppositories, in which a drug
is delivered transurethrally, (alprostadil in MUSE; medicated
urethral system for erections), can be painful or less effective.
Oral corporal pharmacotherapy also has been used. Apomorphine
treatment, in which a pellet is placed under the tongue for
absorption into the blood stream, works by stimulating receptors in
the brain which may then result in an erection five to twenty
minutes after administration. Sildenafil citrate (VIAGRA.TM.,
Pfizer) has become available more recently and has been shown to
help about 70% of men with impotency problems. However, in patients
with preexisting cardiovascular disease, there is a potential for
cardiac risk of sexual activity associated with VIAGRA use.
Further, patients taking any medicines that contain nitrates, which
are often used as treatments for angina (chest pain due to heart
disease), cannot take VIAGRA. Moreover, not all patients respond to
VIAGRA treatment.
Topical/transdermal delivery of vasodilators that stimulate
erectile function is another possibility for treating erectile
dysfunction (e.g., hydralazine; U.S. Pat. No. 4,801,587).
Transdermal delivery of prostaglandins has been shown to be
feasible (Watkinson et al., Int. J. Pharm. 74 (1991) 229-236.,
Uekama et al., J. Pharm. Pharmacol. 44 (1992) 119-121), and
delivery is facilitated by penetration enhancers. It has been shown
that PGE1 permeated across hairless mouse skin in-vitro when
delivered by iontophoresis, but not by passive transport (aqueous
solution used; Saeki et al., Int. J. Pharm. Therapeutics 36 (1996)
525-529). However, the lag time of absorption may be too long for
treatment of erectile disorders, as a response within 5-20 minutes
is desired. When 500 microgram of PGE1 was applied to the genital
area, immediate erection could not be obtained (Chiang et al., Ann.
Acad. Med. Singapore 24 (1995) 767-769).
Thus, in view of the problems associated with current methods for
treating erectile dysfunction by injectable and systemic
pharmacotherapies and prostheses, a need exists for the development
of alternative methods for treating erectile dysfunction. The
present invention satisfies this need and provides related
advantages as well.
SUMMARY OF THE INVENTION
The present invention is based on the development of a non-invasive
method and apparatus for delivery of drugs or genes into the penile
erectile tissue to induce or enhance penile erection, which affords
an alternative treatment for patients afflicted with erectile
dysfunction (ED). Sufficient electric pulses temporarily create new
pathways in the penile skin thereby driving a composition, such as
a vasoactive or androgenic medication, into the corporal
cavernosum.
In a first embodiment, the invention provides an electrical
apparatus for treating erectile dysfunction or inducing or
enhancing erectile function non-invasively in a subject. The
apparatus includes a cuff capable of conforming to the shape of a
penis; and a pulse applicator connected to said cuff capable of
applying an electric pulse of sufficient strength and duration to
the penis for transdermally introducing a composition into the
penis.
In another embodiment, the invention includes a method for treating
erectile dysfunction or for inducing, enhancing or maintaining
erectile function in a subject, comprising applying an electric
pulse to the penis substantially contemporaneously with a
vasoactive or androgenic composition, said electric pulse having
sufficient strength and duration for transdermally introducing an
effective amount of the composition into the penis, thereby
treating erectile dysfunction or inducing, promoting or enhancing
erectile function.
In yet another embodiment, the invention includes a method for
preventing or inhibiting impotence in a subject including applying
an electric pulse to the penis substantially contemporaneously with
a vasoactive or androgenic composition, said electric pulse having
sufficient strength and duration for transdermally introducing an
effective amount of the composition into the penis for preventing
or inhibiting impotence.
The invention further includes a method for delivering a
composition into the penis of a subject including applying an
electric pulse to the penis substantially contemporaneously with
the composition, said electric pulse having sufficient strength and
duration for transdermally introducing the composition into the
penis in an amount greater than passive diffusion.
The invention also includes a kit for treating erectile dysfunction
or inducing or enhancing erectile function. The kit includes, for
example, a package having an electrical apparatus for treating
erectile dysfunction or inducing or enhancing erectile function of
a subject; and instructions for use.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 shows an exemplary electrical apparatus for transdermally
introducing compositions into the penis comprising a cuff, a pulse
applicator and a pulse generator.
FIG. 2 shows an exemplary pulse applicator with incorporated
electrodes and having a VELCRO.TM. fastening means for use in the
electrical apparatus of FIG. 1.
FIG. 3 shows another exemplary electrical apparatus for
transdermally introducing compositions into the penis for
feasibility study on patients (cuff type with integral pulse
applicator).
FIGS. 4A and 4B show the arterial (upper horizontal line) and
penile intracavernosal pressure (lower horizontal line) in a rabbit
in which PGE1 (10 mg/20 .mu.l) was applied to the glans penis and
to the penile shaft and a first electric pulse (of 5.2 ms and 60V)
applied to the glans penis and shaft (pulse indicated by arrow)
produced a sharp increase in intracavernosal pressure resulting in
a full erection (A). After 22 minutes and spontaneous detumescence,
an additional 10 mg PGE1 was applied to the glans and shaft and a
second electric pulse (of 5.2 ms and 60 V) applied to the glans and
shaft produced a sharp increase in intracavernosal pressure
resulting in a full penile erection lasting for 15 minutes (B).
Neither the first nor the second pulse affected arterial
pressure.
FIGS. 5A to 5C show the arterial (upper horizontal line) and penile
intracavernosal pressure (lower horizontal line) in three rabbits
in which PGE1 was applied to the penile shaft and glans followed by
electropulsing as described in Example II. One animal achieved full
penile erection (A), one animal developed partial erection (B), and
one animal showed only minor erectile activity (C). Arrows indicate
the point at which electrical stimulation occurred.
FIGS. 6A to 6C show the arterial and penile intracavernosal
pressure in three rabbits in which trimix (papavarine, phentolamine
and PGE1) was applied to the penile shaft and glans followed by
electropulsing as described in Example II. One animal achieved full
penile erection (A), while the other two animals developed partial
erection (B) and (C). Arrows are as indicated.
FIG. 7 shows a summary of the data shown in FIGS. 5 and 6, as
described in Example II. Vasodilators applied are as indicated on
the X-axis and the numbers for each bar indicate penile
intracavernosal pressure as a Percent (%) of Systemic Aterial
Pressure before (bottom) and after (top) electropulsing.
FIG. 8 shows a summary of the control studies described in Example
III. Penile intracavernosal pressure for each (no electropulsing:
PGE #1, PGE #2, Trimix #1, Trimix #2; and with electropulsing
alone: EP#1 and EP#2) is indicated as the Percent (%) of Systemic
Arterial Pressure (bar). The bottom number for each bar is the
percent before PGE1 or trimix application or electropulsing alone;
the top number for each bar is the percent after PGE1 application,
trimix application or electropulsing, each alone.
FIG. 9 shows the delivery of PGE1 solution across dermatomed human
skin to receptor in glass diffusion cells combined with 30 min of
iontophoresis (PGE1 cumulative amount, .mu.g/cm.sup.2 skin) with
anode in donor (anodic) or cathodes in donor (cathodic) and a
control without iontophoresis (passive) over time (X-axis). Error
bars extend from each point.
FIG. 10 shows the delivery of PGE1 solution with latex or dextran
particles into full thickness human skin by pulsing and subsequent
slow release into receptor solution after mounting on transdermal
diffusion cells. Error bars extend from each point.
FIG. 11 shows release of PGE1 from skin following pulsing of a PGE1
suspension (300 .mu.g/6 .mu.l) into dermatomed skin. Error bars are
as before.
FIG. 12 shows release of PGE1 from pulsed full thickness skin with
or without iontophoresis. Error bars are as before.
FIG. 13 shows that electropulsing at a strength and duration to
introduce a composition into the rabbit penis is well tolerated by
human subjects.
FIG. 14 shows an exemplary transdermal delivery system for ED
(open-condom type device with all function units) in the unwrapped
conformation and as worn (depicting color bands showing patients
the location of electrodes).
DETAILED DESCRIPTION OF THE INVENTION
The present invention is based upon the seminal discovery that
applying a composition to the penile shaft or glans in conjunction
with applying an electrical impulse to the penis is effective for
introducing compositions into the penis. The invention therefore
provides an electrical apparatus for transdermally introducing
compositions into the penis and methods for introducing
compositions into the penis. A method of the invention includes
applying an electric pulse of a sufficient strength and duration to
the penile shaft or glans substantially contemporaneously with a
vasodilator or androgenic composition, thereby transdermally
introducing the composition into the penis. A method of the
invention in which an effective amount of such a composition is
transdermally introduced into the penis is useful for treating
erectile dysfunction or for inducing, enhancing or maintaining
erectile function.
The electrical apparatus and the methods of the invention are
advantageous in several respects. The apparatus and the methods
allow for rapid and non-invasive delivery of a drug into the penis
without the pain and penile fibrosis/scarring that results from
needle injection. The dose of medication needed for local treatment
as compared to systemic treatment is generally lower thereby
minimizing or prevent side effects or other problems associated
with systemic drug delivery. Thus, the apparatus and the methods of
the invention are particularly applicable for treating erectile
dysfunction or for inducing, enhancing or maintaining erectile
function in subjects having a low pain tolerance, who easily scar
or in which the use of systemic drugs is not possible or is
otherwise undesirable. The invention apparatus and methods are
additionally advantageous when used in combination with other
techniques or apparatus (e.g., iontophoresis (IPH), vibration,
phonophoresis, pharmacotherapeutics ( optionally, liposome
encapsulated), penile venous flow restriction devices,) as the
combination can produce an additive or synergistic effect so that
maximal therapeutical effects for treating erectile dysfunction or
for inducing or enhancing erectile function are produced. For
example, successive electropulsing of one vasodilating composition
into the penis followed by a different composition, or a mixture of
different vasodilating compositions can produce a greater effect
than electropulsing a single vasodilating composition alone.
Electropulsing the penis with a vasoactive composition, followed by
iontophoresis, can produce a greater therapeutic effect than either
applying the pulse or iontophoresis alone. Similarly,
electropulsing combined with administering a drug for treating
erectile dysfunction (e.g., VIAGRA.TM.), at doses lower than those
normally associated with clinical efficacy, can produce an additive
or synergistic effect greater than that produced by penile
transdermal drug introduction or VIAGRA.TM. administration alone,
while minimizing side effects due to the lower dose. Furthermore,
electroincorporation (see, e.g., U.S. Pat. No. 5,464,386, which is
hereby incorporated herein in its entirety by reference), or
electropulsing in combination with IPH and liposomal formulation
can enhance delevirey significantly. (see, e.g., Badkar, et al.,
Drug Delivery 6 (1000) 111-115).
As used herein, the terms "impulse," "pulse," "electrical impulse,"
"electrical pulse," "electric pulse," "electropulse" and
grammatical variations thereof are interchangeable and all refer to
an electrical stimulus. Although the various terms are frequently
used herein in the singular, the singular forms of the terms
include multiple pulses. Preferred electrical impulses are pulsed
electric fields applied via electroporation. The pulse can be
unipolar, bipolar, exponential or square wave form.
The term "erectile dysfunction" is used broadly herein, and refers
to either an acute or chronic inability to achieve or maintain an
erection of sufficient rigidity for sexual intercourse. Thus, the
term includes severe cases of chronic impotence as well as single
episodes of impotence in a subject not generally characterized as
impotent. The term "treating" when use in reference to erectile
dysfunction further includes "preventing" or "inhibiting" erectile
dysfunction.
As used herein, the term "erectile function" refers to either an
induction of penile tumescence sufficient to achieve sexual
intercourse, to an increased or enhanced penile tumescence in a
penis that already exhibits tumescence, or to maintenance of penile
tumescence. Generally, erectile function "induced, enhanced or
maintained" will be that sufficient for sexual intercourse.
As used herein, the term "transdermally introducing" and
grammatical variations thereof, refers to the delivery of a
composition into the skin, through/across the skin, or a
combination thereof. An electric pulse that transdermally
introduces a composition into the penis is believed to overcome the
resistance of the skin barrier or alter the permeability of tunica
albuginia. Thus, in a method of the invention in which an
androgenic or vasoactive composition is "transdermally introduced"
into the penis, the composition is driven into or through/across
the penile skin. The "transdermally introduced" composition is
likely driven into the corporal cavernosum, or into the blood
supplying the corporal cavernosum by the pulse(s), to affect the
erectile tissue.
As used herein, the term "subject" refers to any animal that has a
blood vessel. It is envisioned that the methods for inducing or
increasing vasodilation of a vessel and the methods for inducing or
increasing the flow of fluid through a vessel described herein can
be performed on any animal. Preferably, the subject is a human.
The invention provides an electrical apparatus for treating
erectile function or for inducing, enhancing or maintaining
erectile function. The apparatus comprises a cuff capable of
conforming to the shape of a penis and a pulse applicator connected
to said cuff capable of applying an electric pulse of sufficient
strength and duration to the penis for transdermally introducing a
composition into the penis.
An exemplary hand-held electrical apparatus, comprising a mini
pulse generator 100 physically connected to a cuff 102 in
association with an electrode containing pulse applicator (or
sheath) 104, is shown in FIG. 1. The cuff shape will preferably be
cylindrical, although other shapes can be used so long as the shape
is ergonomically compatible with the penis and can function as
described herein. The exemplary pulse applicator comprises a
sheath, optionally disposable, that conforms to the cuff shape
(illustrated but not limited to FIGS. 1 and 2); the sheath contains
an electrode 106 on the inner surface. Depending on the formulation
of the composition to be transdermally introduced, the electrode
can be an insulated or porous meander electrode; a meander
electrode is an interweaving array of metal fingers coated on a
thin film, such as plastic, which can be placed on skin. The sheath
is connected to the mini generator via contacts on the outer
surface of the sheath. The sheath enables one or both sides of the
penile midshaft, penile glans or both midshaft and glans to be in
contact with the electrode, while generally avoiding urethra
contact with the electrode. Prior to use, the sheath is positioned
in the cuff so that contacts located on the outer surface are made
with the mini generator, and the inner surface of the sheath is
positioned to be in contact with the penis; a desired composition
is administered, preferably topically, to the penis. In operation,
the penis is placed longitudinally in the cuff in contact with the
electrodes (as disposed within the sheath) and the cuff is closed
about the penis; the exemplary electrical apparatus has an integral
snap-closure mechanism 108 to secure the cuff in the closed
position thereby ensuring good contact between the electrodes and
the penile glans, shaft, or both, as is shown in FIG. 1. One or
more appropriate electric pulses are then applied, preferably a
pulsed electric field, by depressing an activator button 110; the
exemplary electrical apparatus has the activator button positioned
on the mini-generator.
The aforementioned invention apparatus shown in FIG. 1 is not meant
to be limiting. Thus, other apparatus, additional functional
components and variations thereof are specifically contemplated
herein. For example, a second exemplary apparatus is shown in FIG.
3 that includes several additional components such as a pressure
applicator tube 200 (to improve contact between penile skin and
electrode, or to exert pressure on the penis thereby increasing
transdermal introduction of a composition into the penis), a means
for applying pressure (e.g., a bulb 202), a pressure sensor tube
204 and a sensor gauge 206 (e.g,. indicating if there is a good
contact between penile skin and electrode). In the depicted
embodiment, an infant blood pressure cuff was employed, as it
contains a pressure tube and sensor. The remaining components of
the invention assembly are essentially the same as those described
and depicted in FIG. 1. For example, there is a sheath (or pulse
applicator) 210, comprising electrodes 216, disposed within a
meander strip 214, having an elctrode side 214a and a back side
214b. As shown in FIG. 3, the pulse generator 208, although
operatively connected to the pulse applicator is not physically
attached to the sheath 210 or to the cuff, as in the mini-apparatus
exemplified in FIG. 1. Thus, an invention electrical apparatus may
or may not be physically attached to the pulse generator, but only
need be operatively connected.
Additional functional components that can be added to the invention
electrical apparatus include, for example, an iontophoresis unit
(IPH), which can be used in combination with an electrical impulse
to transdermally introduce a greater amount of the composition into
the penis than pulsing alone, or that can drive the composition
deeper into the penis, if desired. A switching unit, such as an
automated switch, optionally programmable, could be used to control
the time between applying the impulse and applying IPH, as well as
optionally controlling the time during which IPH is applied. Each
parameter will be determined by the composition introduced, the
desired effect, the concentration etc. In one aspect of this
embodiment, electrodes on either side of the penis can be operated
by an electroporation unit and an IPH unit respectively in a
sequential manner. More specifically, two electrodes can be
disposed on either side of the penis (e.g., electrodes 1 and 2 on
the left side and electrodes 3 and 4 on the right side). In
electroporation mode electrode 1 is pulsed against electrode 2,
likewise electrode 3 is pulsed against electrode 4. In IPH mode,
electrode 1 is connected to electrode 2 (with either positive or
negative polarity) while electrode 3 is connected to electrode 4
with an opposite polarity; then electrodes 1 and 2 will be pulsed
against electrodes 3 and 4. Of course, these operation parameters
can be set or programmed into the mini-generator.
A vibration unit also can optionally be included in the apparatus,
which can be used in combination with an electrical impulse to
transdermally introduce a composition into the penis, if desired. A
phonophoresis unit, which can transdermally introduce a composition
into the skin by means of ultrasound, also can optionally be
included in the apparatus, if desired. Thus, by applying vibration
or ultrasound before, after or during pulsing and/or iontophoresis
on the penile glans or midshaft, the composition can be driven
deeper into the penis or a greater amount of the composition can be
driven into the penis than pulsing alone. As above, a switching
unit, such as an automated switch, optionally programmable, could
be used to control the time between applying the impulse and
applying vibration or ultrasound, as well as optionally controlling
the time during which impulse, vibration or ultrasound is
applied.
A means for administering a composition can optionally be included
in the electrical apparatus, which can be used to administer the
composition to the penis prior to, substantially contemporaneously
with, or after applying an electric pulse, iontonophoresis,
vibration or ultrasound, in their various embodiments. Depending on
the specific formulation, a composition can be incorporated into a
patch reservoir (e.g., as a nicotine patch), which is then attached
both to the electrode and the penis. Formulations employed for IPH
are advantageously used in this manner.
As used herein, the term "substantially contemporaneously" means
that the electric pulse and the composition are applied to the
penis reasonably close together in time. Preferably, the
composition is administered prior to or concurrently with
electropulsing. When applying multiple electrical impulses, the
composition can be administered before or after each of the pulses,
or at any time between the electrical pulses. When applying
iontophoresis, vibration or ultrasound, the composition can be
administered before or after each, and at any time between.
Restricting venous outflow from the penis can induce, enhance or
maintain erectile function by maintaining the imbalance between
arterial inflow and venous outflow, or by inhibiting outflow from
the penis of a vasodilator or an androgenic composition
transdermally introduced into the penis as set forth herein. Thus,
a means for restricting venous flow from the penis optionally can
be included in an invention apparatus as disclosed herein. For
example, a mechanical constriction device, band, strap or clamp can
be physically attached to the apparatus, such as the cuff, to be
secured around the penis at the base (e.g., as with a tourniquet).
Venous outflow can be controlled by varying the degree of penile
constriction. The band or strap can be flexible or elastic (e.g.,
latex, butyl rubber, synthetic or natural elastomers etc.).
Optionally, a tubular band of an appropriate thickness can be used
to enable inflation of the tube band to adjust the degree
constriction thereby controlling the amount of venous outflow from
the penis. A bulb at one end of such a tube band having a closed
opposing end can be used to apply pressure within the tube band
thereby inflating the band; an optional pressure sensor can monitor
the amount of pressure and a release valve or other appropriate
pressure release mechanism can additionally be included to decrease
or eliminate penile constriction when sufficient erection is
attained or so as to not cause discomfort. The term "elastic" or
"elasticity" as used herein refers to the ability of a solid
material to change shape or size under opposing forces, to sustain
such deformation without permanent loss of size or shape, and to
recover most or all of its original configuration when the forces
are removed. Preferred elastic bands or straps are flexible and
capable of regaining their original shape after being deformed
within their elastic limits; elasticity of a material can be
quantified in a variety of ways, and can be modified by altering
the composition. The band, strap, clamp etc. can be covered in
fabric or otherwise modified to increase user comfort. Various flow
control devices that can be used to control penile venous flow are
known in the art and it is specifically contemplated that the
invention electrical apparatus can be modified to incorporate such
devices, if desired (see e.g., U.S. Pat. No. 5,855,548).
In addition to the various functional components that can be added
to the invention electrical apparatus, each of the essential
components of the invention apparatus can be modified, or can have
additional functional components. For example, in the exemplary
hand-held mini pulse generator/power source shown in FIG. 1, the
pulse applicator 104 comprising the sheath is separable from the
cuff 102, and the mini generator 100 is affixed to the cuff.
However, the pulse applicator optionally can be affixed to the
cuff, and the mini generator optionally can be separable from the
cuff. Additionally, the nature of the electrode that can be used in
the pulse applicator can be varied so long as it is capable of
delivering a sufficient electric pulse as set forth herein. Thus, a
variety of electrode types and configurations are contemplated in
the invention apparatus.
In one embodiment, the electrode is a wire electrode (useful for in
vitro studies, and the like). In another embodiment, the electrode
is a plurality of electrodes (e.g., a micropatch electrode as
described in U.S. patent application Ser. No. 09/134,245, filed on
Aug. 14, 1998, which is hereby incorporated herein in its entirety
by reference). In still yet another embodiment, the electrode
comprises a meander electrode (e.g., an array of interweaving
electrode fingers, with a typical electrode width in the range of
about 0.2 up to about 1 mm, and an electrode gap of about 0.2 mm,
wherein the gap can be filled with an electrically insulating
substance). In an additional embodiment, the electrode is a porous
electrode. The various electrodes used herein are preferably
insulated to protect against excess heat or burning, current
leakage, shock, etc. Appropriate electric pulsing parameters are
set forth herein or can be determined using the teachings herein
and, in view of these parameters, the skilled artisan can select
among various suitable electrode types (e.g., ceramic, metal, etc.)
and configurations (single wire, multiple wire, etc.) available in
the art.
The cuff can be manufactured of essentially any material compatible
with applying an electrical impulse to the penis. The cuff can be
made of a single material type or can be made of multiple material
types. In one embodiment, the cuff is manufactured of a single
flexible cushioned or compressible material. In another embodiment,
the inner cuff, which contacts the penis, is made of a cushioned or
compressible material and the outer cuff is made of a rigid
material, such as plastic, metal, an alloy, or a combination
thereof. Although the cuff of the exemplified apparatus has a
relatively fixed size, preferably the cuff is adjustable or
compressible so as to accommodate various penis sizes and different
states of penile tumescence. For example, in one embodiment, the
apparatus has an inner cuff separable from an outer cuff, and has
variously sized inner cuff pieces (e.g, different thickness),
optionally compressible, that can be inserted into the outer cuff
so as to be adjustable with respect to cuff size. Preferably, the
various cuff embodiments of the invention apparatus are
hypo-allergenic, non-allergenic or so modified to be
non-allergenic.
The invention apparatus can have an indicating means to ensure
proper positioning of the apparatus relative to the penis. For
example, a visible band on the apparatus can indicate where the
apparatus should be located relative to the shaft and/or glans. A
visible band additionally can indicate proper penile location
relative to the electrodes used for applying the pulse to the
penis. For example, referring to FIG. 14, two differently colored
bands 302 and 304, each of which indicate the electrodes for the
shaft and for the glans respectively, can be included.
Alternatively, the apparatus can be modified or manufactured to
have sufficient transluscence (e.g., clear polycarbonate) so that
the penis can be visualized in order to achieve proper positioning.
In another alternative, a "closed condom" or "cone" shaped
apparatus can be manufactured such that inserting the penis all the
way to the end of the cone ensures proper positioning within the
apparatus (See, e.g., FIG. 14 showing the open condom embodiment,
as worn, and as viewed from the inside in an opened view).
Mere pressure, such as that provided by hand, can be sufficient to
secure the invention electrical apparatus about the penis.
Alternatively, a fastening means, optionally adjustable, can be
used for securing the electrical apparatus. For example, the
exemplified apparatus has a snap-closure fastening means attached
thereto (e.g., the cuff, FIG. 1). Additional contemplated fastening
means include, for example, VELCRO, snap, buckle, clip, clamp,
adhesive tape and coupling mechanism. An adjustable fastening means
has the advantage of being able to accommodate various penis sizes
and different states of penile tumescence as well as exerting
pressure on the penis to drive more of the composition into the
penis, or drive the composition into deeper areas of the penis.
Alternatively or in addition, the pulse applicator, if desired, can
be modified to include a fastening means as described herein. In a
particular aspect, a pulse applicator fastening means is VELCRO.TM.
(FIG. 2).
As described herein, the separable pulse applicators optionally are
disposable. Thus, in accordance with the present invention, a kit
comprising at least one pulse applicator is further provided. The
kit contains appropriate packaging material and instructions
relevant to the enclosed pulse applicator. Preferably, the pulse
applicator has been sterilely manufactured or treated to be sterile
and packaged to maintain sterility. In addition to the above
described components, the kit optionally contains one or more
androgenic or vasoactive compositions, such as those described
herein or known in the art, for use with the enclosed pulse
applicator in the electrical apparatus.
The invention apparatus can have a variety of other "user friendly"
functionalities in addition to the optional controlling means
("activator button") for applying an electric pulse, indicating
means and fastening means. For example, the apparatus can have an
indicating means for indicating apparatus ready, the various pulse
parameter settings (e.g., voltage, capacitance, pulse duration,
time delay between pulses, pulse wave type), pulse(s) applied,
parameters of the applied pulse(s) (e.g., voltage, capacitance,
pulse duration, pulse wave type, number of pulses) or a combination
thereof. Such indicating means can be visual, audible, or a
combination thereof. For example, a single audible "beep" can
indicate that the "apparatus is ready," two audible "beeps" can
indicate that a pulse has been correctly applied and three audible
"beeps" can indicate a malfunction or that the pulse was not or was
improperly applied. Visual indicating means include analog or
digital alpha-numeric displays (e.g., LCD, LED and the like), as in
watches, and further can include illuminating means for low light
visualization, for example, by white light, electroluminescent
backlighting for LCD or electroluminescent lamps (i.e.
INDIGLO.TM.), or by various fluorescent or radioactive illuminating
compositions, and the like.
Additional "user friendly" functions include the aforementioned
controlling means for applying an electric pulse (e.g., pushbutton,
knob, lever switch, dial and the like) as well as means for
adjusting parameters (e.g., pushbutton, knob, lever switch, dial
and the like) including, for example, pulse duration, voltage,
capacitance, field strength, number, wave type and penile location
(e.g., one or both sides of the midshaft or shaft, the glans, or a
combination thereof). Means for adjusting, setting, storing or
retrieving one or more pulse parameters also are included herein.
Such means include traditional mechanical electronic controls
(e.g., a selector switch controlling each parameter in which the
switch has a plurality of settings; exemplary pulse length
settings, 5 msec, 10 msec, 25 msec, 35 msec, 50 msec, for example.)
as well as a chip control (e.g., silicon wafer types commonly used
in the computer industry) which is controlled, for example, by a
pushbutton interface, as in watches for example. A chip, optionally
removable from the apparatus or, user and/or manufacturer
programmable for control of the various pulse parameters set forth
herein also is contemplated. Storage capacity of such a chip is
sufficient to provide virtually unlimited fine control of the
various parameters, as well as storing different pulse parameter
settings for different compositions, users and the like. As each of
the various electronic functionalities of the invention apparatus
described herein can be controlled or managed by a computer chip, a
chip affords the option of additionally incorporating software, if
desired, said software optionally user programmable.
In addition to efficacy, both sensation and user safety are
important. Thus, in another embodiment, the invention further
provides an apparatus having means for preventing applying excess
pulse voltage, duration, field strength and/or number. Any means
which passively or actively interrupts or disrupts the electric
circuit, including fuses, circuit breaker switches, and the like,
or devices that actively monitor the various pulse parameters and
interrupt or disrupt the electric circuit to prevent excess pulse
voltage, duration, field strength, pulse number from being applied
can be incorporated into the circuit path. Those skilled in the art
of electrical devices will know of other protective elements that
prevent applying excess pulse voltage, duration, field strength or
number.
The electric pulse can be provided by any electronic device that
provides an appropriate electric pulse or electric source
sufficient for transdermally introducing a composition into the
penis. Suitable electric pulses for transdermally introducing
compositions into the penis therefore include, for example, square
wave pulses, exponential waves, unipolar oscillating wave forms,
bipolar oscillating wave forms, other wave forms generating
electric fields, or a combination of any of these forms. Each pulse
wave form has particular advantages; square wave form pulses
provide increased efficiencies in transporting compounds into the
cells in comparison to exponential decay wave form pulses, and the
ease of optimization over a broad range of voltages, for example
(Saunders, "Guide to Electroporation and Electrofusion," 1991, pp.
227-47). Preferably, the waveform used is an exponential or a
square wave pulse.
An exemplary electric impulse for transdermally introducing a
composition into the penis is a pulsed electric field, such as that
provided by an electroporation apparatus. Exemplary pulse
generators capable of generating a pulsed electric field include,
for example, the ECM600, which can generate an exponential wave
form, and the ElectroSquarePorator (T820), which can generate a
square wave form, both of which are available from BTX, a division
of Genetronics, Inc. (San Diego, Calif.). Additional
electroporation type apparatus are commercially available and can
be used to generate the pulse for the invention apparatus and in
practicing the invention methods. Such pulse generators can be
operatively connected to the pulse applicator as shown in FIG. 3,
for example, or alternatively can be physically connected to the
cuff or pulse applicator. A pulse generator, physically connected,
is preferably portable or lightweight, as in the exemplary mini-
pulse generator 100 (FIG. 1), and an optional portable DC power
source, such as batteries, optionally being rechargeable, can be
included to provide the power source to the pulse generator.
The results showing that an electrical impulse applied to the penis
transdermally introduces topically applied PGE1 or trimix
(papavarine, phentolamine and PGE1) into the penis thereby inducing
or enhancing erectile function are shown in Examples I to III and
in FIGS. 4 to 8. Exemplary pulse parameters for transdermally
introducing a composition into rabbit penis, human skin and human
penile skin are described herein in Examples I to IV.
Thus, in accordance with the present invention, methods for
delivering a composition into the penis of a subject are provided.
In one embodiment, the method comprises applying an electric pulse
to the penis substantially contemporaneously with a composition, in
which the electric pulse has sufficient strength and duration for
transdermally introducing the composition into the penis in an
amount greater than passive diffusion.
In another embodiment, methods for treating erectile dysfunction or
for inducing, enhancing or maintaining erectile function in a
subject are provided. A method comprises applying an electric pulse
to the penis substantially contemporaneously with a vasoactive or
androgenic composition of sufficient strength and duration for
transdermally introducing an effective amount of the composition
into the penis, thereby treating erectile dysfunction or inducing,
enhancing or maintaining erectile function.
As the invention methods for treating erectile dysfunction or for
inducing, enhancing or maintaining erectile function also prevent
or inhibit impotence, the invention further provides methods for
preventing or inhibiting impotence in a subject. The method
comprises applying an electric pulse to the penis substantially
contemporaneously with a vasoactive or androgenic composition, said
electric pulse having sufficient strength and duration for
transdermally introducing an effective amount of the composition
into the penis for preventing or inhibiting impotence. The methods
for preventing or inhibiting impotence in a subject can be modified
as described herein as with the various embodiments of the methods
for treating erectile dysfunction or for inducing, enhancing or
maintaining erectile function.
In one aspect, the electric pulse is applied to the penile glans.
In another aspect, the electric pulse is applied to one side of the
penile shaft. In various other aspects, the pulse is applied to
both sides of the shaft, either side of the midshaft, both sides of
the midshaft and both the penile glans and the midshaft.
Generally, the pulse strength applied to the penis will range from
about 25 to about 200 volts, preferably from about 40 to about 100
volts and more preferably from about 50 to about 80 volts. The
pulse duration generally will be from about 100 microseconds
(.mu.s) to 100 milliseconds (ms), preferably from about 500 .mu.s
to about 50 ms and more preferably from about 1 ms to 30 ms. The
capacitance will generally range from about 100 to about 1000
.mu.F, preferably from about 200 to about 800 .mu.F, more
preferably from about 400 to about 1000 .mu.F. There can be from
about 1 to about 25 pulses applied. Preferably, the number of
pulses is from about 1 to about 10 pulses and more preferably from
about 1 to about 6 pulses per cycle. Most preferably, 5 to 15 pulse
cycles are applied.
The voltage, waveform type, pulse duration, capacitance, field
strength and the number of pulses applied will vary depending on
the location of the pulse and the nature of the composition to be
transdermally introduced. For example, as the glans is more
sensitive than the shaft, low voltage and short pulses, preferably
in combination with iontophoresis, is preferred on the glans. The
glans is less electrically resistant than the shaft and therefore,
less voltage may be needed to transdermally introduce compositions
into the glans. For the shaft, relatively higher voltages and
longer pulses are tolerable. Particular electrical parameters for
transdermally introducing a composition into the penis, other than
those exemplfied herein, can be empirically determined if
necessary, in view of the teachings herein and of the general
knowledge of those having skill in the art, for example, relating
to the electroporation of mammalian cells in vivo.
The terms "androgenic" or "vasoactive" composition refers to a
drug, agent, compound or chemical that has or that can produce or
enhance one or more activities characterized as "androgenic" or
"vasoactive" as is known in the art. When administered to a
subject, such compositions induce or enhance an "androgenic" or
"vasoactive" effect. As used herein, a "vasoactive composition"
means a substance having the capability of altering the physiologic
state, especially the tone and diameter, of a vessel. Thus, a
"vasodilator" is a composition that induces or enhances vessel
relaxation or dilation and a "vasoconstrictor " is a composition
that induces or enhances vessel rigidity or constriction. As used
herein, an "androgenic composition" refers to a substance having or
capable of enhancing an erection. Various androgenic and
vasodilating drugs and other compositions having such properties
are described herein and are further known to those skilled in the
art and as such are applicable in using the invention apparatus and
in practicing the invention methods.
Although not wishing to be bound by any theory, it is believed that
the common channels for the drainage of the glans, corpus
spongiosum, and the corpus cavernosum are the route for drug
transfer from the spongiosal to the cavernosal compartment (Vardi
et al., Urology vol. 49 (1997)). Thus, in all likelihood, the
compositions transdermally introduced into the penis for treating
erectile dysfunction or for inducing, enhancing or maintaining
erectile function are driven into the corpus cavernosum or into the
blood vessels that supply the corpuscavernosum thereby producing a
local effect or function within the erectile tissue.
As used herein, the term "local," when used in reference to a
composition, refers to its function in a particular region. Thus, a
vasoactive composition transdermally introduced into the penis is
believed to exert its vasoactive function within the penis.
Nevertheless, the skilled artisan will recognize that some
transdermally introduced compositions may have a systemic effect or
function, such that after transdermally introducing the composition
into the penis, the composition is distributed to other areas of
the subject thereby producing or contributing to treating erectile
dysfunction or inducing, enhancing or maintaining erectile function
by acting at a site other than the penis. As used herein, the term
"systemic," when used in reference to a composition, means that the
composition functions outside the penis. It is specifically
contemplated that compositions that function systemically are
included herein in addition to those functioning locally or both
systemically and locally.
Any composition can be used in the methods of the invention, so
long as the composition, when transdermally introduced into the
penis, is capable of treating erectile dysfunction or inducing,
enhancing or maintaining erectile function, as set forth herein.
Compositions contemplated for use include drugs (e.g., vessel
vasodilators and androgenic compositions), polynucleotides (e.g.,
genes used in gene therapy, for example, those that are involved in
the erectile function biochemical pathways or those that encode
vasoactive or androgenic polypeptides or fragments thereof;
antisense nucleotides to vasoconstrictor polypeptide including RNAi
antisense; ribozymes), polypeptides (e.g., vasoactive peptides and
proteins, functional derivatives thereof including, for example,
protease resistant analogs). Modified compositions that are
biologically functional analogs or derivatives of the compositions
described herein (salts, esters etc.) also are useful in the
methods of the invention (see also e.g., Trampota et al., U.S. Pat.
No. 5,618,959, which describes various PGE.sub.1 and PGE.sub.2
analogs and derivatives).
Specific vasoactive compositions include, for example, prazosin and
papeverine; naturally occurring protaglandins, PGE.sub.1,
PGE.sub.2, PGE.sub.1, PGA.sub.1, PGB.sub.1, PGF.sub.1,
19-hydroxy-PGA.sub.1, 19-hydroxy-PGB.sub.1, PGE.sub.2, PGA.sub.2,
PGB.sub.2, 19-hydroxy-PGA.sub.2, 19-hydroxy-PGB.sub.2, PGE.sub.3,
PGF.sub.3, PGI.sub.1, PGI.sub.2 ; prostaglandin derivatives,
carboprost tromethamine, dinoprost tromethamine, dinoprostone,
lipoprost, gemeprost, metenoprost, sulprostone, tiaprost; nitric
oxide releasing agents, nitroglycerin, isosorbide dinitrate,
erythrityl tetranitrate, amyl nitrate, sodium nitroprusside,
molsidomine, (Z)-1-{N-methyl-N-[6-(N-methyl
-ammoniohexyl)amino]}diazen-1-ium-1,2-diolate (MAHMA/NO),
(Z)-1-[N-(3-ammoniopropyl)-N-(n-propyl)amino]diazen-1-ium-1,2-diolate
(PAPA/NO),(Z)-1-{N-[3-aminopropyl]-N-[4-(3-aminopropylammonio)
butyl]-amino}diazen-1-ium-1,2-diolate (SPER/NO), sodium
(Z)-1-(N,N-diethylamino)diazenium-1,2-diolate (DEA/NO), linsidomine
(SIN-1), S-nitrosothiols, S-nitroso-N-acetyl-D,L-penicillamine
(SNAP), S-nitroso-N-cysteine and S-nitroso-N-glutathione (SNO-GLU);
vasoactive intestinal peptide agonists and derivatives thereof;
smooth muscle relaxants; leukotriene inhibitors; calcium channel
blockers; .alpha.1-adrenergic antagonists; .alpha.2-adrenergic
agonists; phosphodiesterase inhibitors; antihypertensive agents
such as angiotensin-converting enzyme (ACE) inhibitors and
angiotensin II receptor antagonists; phenoxybenzamine, dibenamine,
doxazosin, terazosin, phentolamine, tolazoline, prazosin,
trimazosin, alfuzosin, indoramin, ergotamine analogs, ergotamine
analogs, acetergamine, brazergoline, bromerguride, cianergoline,
delorgotrile, disulergine, ergonovine maleate, ergotamine tartrate,
etisulergine, lergotrile, lysergide, mesulergine, metergoline,
metergotamine, nicergoline, pergolide, propisergide, proterguride,
terguride, diazoxide, hydralazine and minoxidil, nimodepine,
pinacidil, cyclandelate, dipyridamole, isoxsuprine, chlorpromazine,
haloperidol, yohimbine, trazodone; dopamine antagonists such as
apomorphine and bromocriptine; and opioid antagonists such as
naltrexone. Other vasoactive compositions which can be appropriate
for use may be found, for example, in Remington's Pharmaceutical
Sciences, 18th ed., Mack Publishing Co., Easton, Pa., 1990; The
Merck Index, 12th ed., Merck Publishing Group, Merck & Co.,
Inc., Whitehouse, N.J., 1996; and 51st ed. Physicians Desk
Reference, Medical Economics Data Co., Montvale, N.J., 1997, which
are herein incorporated by reference.
Suitable androgenic compositions include, for example,
androsterone, testosterone, dihydrotestosterone, testosterone
analogs such as dehydroepiandrosterone (DHEA) and DHEA sulfate,
enanthate, propionate, cypionate esters of testosterone,
phenylacetate esters of testosterone, testosterone alkyls,
methyltestosterone, testolactone, oxymetholone and fluoxymesterone.
Other androgenic compositions which may be appropriate for use can
be found, for example, in Remington's Pharmaceutical Sciences,
supra; 1997 Physicians Desk Reference, supra; and The Merck Index,
12th ed., supra.
The compositions used with the invention electrical apparatus and
in the invention methods will be transdermally introduced into the
penis in an amount effective to produce a desired therapeutic
effect, i.e., an amount sufficient to induce, enhance or maintain
an erection sufficient for sexual intercourse. As used herein, the
term "effective" means an amount of drug or pharmacologically
active agent that is sufficient to provide the desired effect
(e.g., an androgenic or vasoactive effect) in which the signs or
symptoms of the clinical situation are ameliorated (e.g.,
sufficient erectile dysfunction is ameliorated so as to enable
sexual intercourse). The amount should not be so large as to cause
excessive adverse side effects, such as skin irratation, burning or
tissue damage. The amount required will vary from subject to
subject, depending on the species, age, and general condition of
the subject (physiological and psychological), the severity of the
condition being treated (e.g., chronic vs. acute erectile
dysfunction), the drug or agent being employed, the mode of
administration (e.g., if an oral drug such as VIAGRA is
co-administered in conjunction with electropulsing, less vasoactive
or androgenic composition may be required; the alternative also is
true), etc. Thus, although it is not possible to specify an exact
"effective amount," an appropriate "effective" amount in any
individual case may be determined by one of ordinary skill in the
art using the teachings herein. For example, by visual inspection
or by measuring penile hemodynamic parameters in response to
various amounts of the composition, an effectivew amount can be
readily determined. The amount can be adjusted by the individual
or, in the event of any complication, by the physician.
The compositions used in a method of the invention are preferably
administered by topical application to the penile skin. The term
"topical" is used herein to refer to administration of a
composition on the surface of the skin or mucosa which can be
applied via direct application (i.e. spreading), via a drug
impregnated skin patch (as in the nicotine patch, for example), or
by an aerosol or other misting device, for example. Other modes of
administration also are included, for example, by injection
intravenously, intraperitoneally, intramuscularly, subcutaneously,
intracavity, etc. Compositions also can be administered into the
urethra, for example, with a suppository or urethral cathete having
at least one port for introducing the composition into the
urethra.
Androgenic and vasoactive compositions, when administered in a
method of the invention, will generally be in "pharmaceutically
acceptable" or "physiologically acceptable" formulations for
therapeutic use. As used herein, the terms "pharmaceutically
acceptable" and "physiologically acceptable" refer to carriers,
diluents, excipients and the like that can be administered to a
subject, preferably without excessive adverse side effects (e.g.,
for a topically applied formulation, skin rash, irritation, etc.).
Particular formulations include aqueous or non-aqueous solutions,
suspensions, emulsions, waxes, creams, lotions, oils or other
liquid and cosmetic formulations suitable for topical application
known in the art. Such formulations are or can be made compatible
with applying an electrical impulse,. For example, the conductivity
should not be too high to produce heat or electrical arching or too
low to provide resistance thereby inhibiting delivery of the pulse
to the skin. Examples of non-aqueous solvents are propylene glycol,
polyethylene glycol (PEG) in its various molecular weights (e.g.,
PEG 400, PEG 400 monostearate, PEG 4000 etc.), glycerine, polyvinyl
pyrrolidine (PVP), polyvinyl alcohol (PVA), mannitol, vegetable
oils such as olive oil, and injectable organic esters such as ethyl
oleate, and the like. Aqueous carriers include water,
alcoholic/aqueous solutions, emulsions or suspensions, including
saline and buffered media. Vehicles include sodium chloride
solution, Ringer's dextrose, dextrose and sodium chloride, lactated
Ringer's, or fixed oils. Intravenous vehicles include fluid and
nutrient replenishers, electrolyte replenishers (such as those
based on Ringer's dextrose), and the like. Preservatives,
surfactants and other additives may also be present such as, for
example, antimicrobial, anti-oxidants (e.g., BHT, BHA), chelating
agents (e.g. EDTA, EGTA), and inert gases and the like. It is also
possible to entrap a vasoactive or androgenic composition into
micro-capsules prepared by coacervation techniques or by
interfacial polymerization, for example, by the use of
hydroxymethylcellulose or gelatin-microcapsules or
poly(methylmethacrolate) microcapsules, respectively, or in a
colloid drug delivery system. Colloidal dispersion systems include
macromolecule complexes, nano-capsules, microspheres, and
lipid-based systems including oil-in-water emulsions, micelles,
mixed micelles, and liposomes (e.g., stabilized liposome
formulations of vasoactive intestinal peptide). The preparation of
an appropriate pharmaceutical formulation for therapeutic use is
well within the general knowledge in the art (see e.g., Remington's
Pharmaceutical Sciences, supra; 1997)
The above-described compositions and others not specifically
described herein are useful in various clinical situations and can
be administered alone, or in a combination with other compositions
by a method of the invention. Combining low dose of oral pills with
electropulsing can provide an additive or synergistic effect in the
methods for treating erectile dysfunction or for inducing,
enhancing or maintaining erectile function while minimizing some of
the side effects of oral therapy and are therefore specifically
included. An additive or synergistic effect also can be produced by
administering a vasoactive or androgenic composition to the subject
by injection or transurethrally in another embodiment. Vacuum
treatment and/or topical cream can be employed with
electrostimulation.
Accordingly, in another embodiment, the invention provides a method
for treating erectile dysfunction or for inducing, enhancing or
maintaining erectile function by applying an electric impulse
having sufficient strength and duration for transdermally
introducing an effective amount of a vasoactive or androgenic
composition into the erectile tissue in combination with
administering a vasoactive or androgenic composition orally, by
injection or transurethrally, or topical cream or vacuum, thereby
treating erectile dysfunction or inducing, enhancing or maintaining
erectile function.
In addition, electrically-induced transdermal introduction of a
vasoactive or androgenic composition into the penis can be
increased over that of electropulsing alone by a variety of other
means. For example, applying pressure on glans or midshaft can
provide an additional driving force to transport drug into the
glans and cross tunica albuginia, or into the midshaft. Restricting
venous flow from the penis by applying a contriction at the base of
penis prior to or after electropulsation using a penile rubber
band, for example, can prevent penile venous flow while medication
is administered and subsequently result in a better degree and
duration of erection.
Applying iontophoresis of the glans, midshaft or both, before or
after electropulsing the glans, midshaft or both, can augment
electrically induced transdermal introduction of a vasoactive or
androgenic composition. Similarly, applying vibration or
phonophoresis to the glans or midshaft or both prior to or after
electropulsing can drive medications into deeper layers of the
penis, such as into the spongiosum or tunica albuginia. Alone, or
in any combination, these additional techniques can be used in
conjunction with electropulsing to transdermally introduce a
composition into the penis (e.g., electropulsing with
iontophoresis, restricting venous flow or vibration; electropulsing
with iontophoresis and restricting venous flow, and so forth).
A "permeation enhancer" also can be included with electropulsing to
increase transdermal introduction of a composition into the penis.
As used herein, the term "permeation enhancer" refers to any action
(e.g., mechanical, physical, chemical) or any composition that can
increase or "augment" transdermally introducing a composition into
the penis. The term "augment," when used herein as a modifier of
transdermal introduction, means that the rate (over time) or amount
of composition transdermally introduced into the penis via
electropulsing is greater than that produced by electropulsing in
the absence of the permeation enhancer. Thus, administering a
permeation enhancer prior to, substantially contemporaneously with
or after applying a vasoactive or androgenic composition to the
penis may "augment" electrically induced transdermal introduction
of the composition into the penis. Alternatively, a permeation
enhancer can be mixed with the composition in the pharmaceutical
formulation to be transdermally introduced. Permeation enhancer
compositions that increase skin permeability include, for example,
alcohols (e.g., methanol), alkyl methyl sulfoxides (e.g., DMSO),
pyrrolidones (e.g., 2-pyrrolidone), surfactants, urea, glycerol
monolaurate, polyethylene glycol monolaurate, glycerol monolaurate,
docainehydrochloride, hydrocortisone, menthol, methyl salicylate,
and the like. Permeation enhancers further include mechanical or
physical actions that function in association with an electrical
impulse (i.e., generally require applying an electrical pulse to
augment transdermal introduction of the compositions into the
penis; e.g., vibration).
The following examples are intended to illustrate but not limit the
invention. While they are typical of those that might be used,
other procedures and applications of the invention methods known to
those skilled in the art may alternatively be used.
EXAMPLE I
This example describes initial studies of topical application of
PGE1 on the penile glans, shaft or both of rabbits followed by
application of a pulsed electric field, and the change in
intracavernosal pressure associated with penile erection produced
in response. Although rabbits were used in these studies, dogs,
cats, and monkeys are also useful animal models for use in
research.
Three New Zealand White rabbits (n=3) weighing between 3-3.5 kg
were used for these studies. Briefly, various concentrations of
PGE1 were topically applied to the penis (shaft, glans or both) of
rabbits anesthetized with intravenous administration of sodium
pentobarbital. The electric pulse was applied by a meander
electrode placed around the penis connected to a BTX 600 pulse
generator (Genetronics, Inc., San Diego, Calif.). Carotid artery
was dissected for on-line measurement of systemic arterial
pressure. A 21 gauge minicatheter was inserted intracavernosally
for measurement of intracavernosal pressure. To ensure erectile
potency, rabbits #2 and #3 were intracavernosally injected with
papaverine and phentolamine injection, which caused a full penile
erection in both rabbits. The procedures performed on the glans
penis or on the penile shaft while recording systemic blood
pressure and intracavernosal pressure are as follows:
1. Application of electric pulse alone (without PGE1).
2. Topical application of PGE1 alone (without electrical
pulse).
3. Topical application of PGE1 in conjunction with electric
pulse.
Rabbit #1
Pulse stimulation alone at 13 ohm, 800 .mu.F and 90V on glans penis
did not affect arterial blood pressure while causing a decrease in
intracavernosal pressure from 25 mm Hg to 10 mm Hg. As those of
skill in the art will understand, the resistance can be multiplied
by the capacitance and the result divided by one thousand to give
the pulse time in milliseconds. PGE1 (1 mg/20 .mu.l or 5 mg/20
.mu.l) alone on glans penis did not affect arterial or
intracavernosal pressure. PGE1 (1 mg/20 .mu.l) on glans penis and
pulse stimulation on glans penis at 13 OHM, 800 .mu.F and 90V
caused a slight increase in arterial pressure while causing a
decrease in intracavernosal pressure from 28 mm Hg to 10 mm Hg.
PGE1 (5 mg/20 .mu.l) on glans penis and pulse stimulation on glans
penis at 13 OHM, 400 .mu.F and 60V did not affect arterial pressure
while causing an increase in intracavernosal pressure from 18 mm Hg
to 32 mm Hg. Response duration was 96 seconds. A second pulse
stimulation at 13 OHM, 400 .mu.F and 60V with the same
concentration of PGE1 (5 mg/20 .mu.l) on the glans caused an
increase in intracavernosal pressure from 20 mm Hg to 32 mm Hg.
Response duration was 115 seconds.
Rabbit #2
Pulse stimulation alone at 13 OHM, 400 .mu.F and 60V on glans penis
did not affect arterial blood pressure or intracavernosal pressure.
PGE1 (10 mg/20 .mu.l) alone on glans penis did not affect arterial
or intracavernosal pressure. PGE1 (10 mg/20 .mu.l) on glans penis
and pulse stimulation on glans penis at 13 OHM, 400 .mu.F and 60V
did not affect arterial pressure while increasing intracavernosal
pressure from 15 mm Hg to 27 mm Hg. Response duration was 1 minute.
A second pulse stimulation at 13 OHM, 400 .mu.F and 60V in the
presence of an additional 2 mg PGE1 on glans penis caused an
increase in intracavernosal pressure from 22 mm Hg to 32 mm Hg.
Response duration was 95 seconds.
Pulse stimulation alone at 13 OHM, 400 .mu.F and 60V on penile
shaft did not affect arterial blood pressure or intracavernosal
pressure. PGE1 (5 mg/20 .mu.l) alone on penile shaft did not affect
arterial or intracavernosal pressure. PGE1 (5 mg/20 .mu.l) on
penile shaft and pulse stimulation on penile shaft at 13 OHM, 400
.mu.F and 70V did not affect arterial pressure while causing an
increase in intracavernosal pressure from 20 mm Hg to 28 mm Hg.
Response duration was 32 seconds. A second pulse stimulation at 13
OHM, 400 .mu.F and 60V on penile shaft caused an increase in
intracavernosal pressure from 26 mm Hg to 37 mm Hg. Response
duration was 45 seconds.
Rabbit #3
Pulse stimulation alone at 13 OHM, 400 .mu.F and 60V on glans penis
did not affect arterial blood pressure or intracavernosal pressure.
PGE1 (5 mg/20 .mu.l) alone on glans penis did not affect arterial
or intracavernosal pressure. PGE1 (5 mg/20 .mu.l) on glans penis
and pulse stimulation on glans penis at 13 OHM, 400 .mu.F and 60V
did not affect arterial pressure while causing only a minor
increase (5 mm Hg) in intracavernosal pressure. A second pulse
stimulation at 13 OHM, 400 .mu.F and 60V on glans penis in the
presence of an additional 5 mg PGE1 on the glans increased
intracavernosal pressure from 15 mm Hg to 23 mm Hg. Response
duration was 30 seconds.
PGE1 (10 mg/20 .mu.l) on glans penis and pulse stimulation on glans
penis at 13 OHM, 400 .mu.F and 50V did not affect arterial pressure
while causing only a minor increase (7 mm Hg) in intracavernosal
pressure. PGE1 (10 mg/20 .mu.l) on glans penis and pulse
stimulation on glans penis at 13 OHM, 200 .mu.F and 50V did not
affect arterial pressure but increased intracavernosal pressure
from 15 mm Hg to 20 mm Hg. A second pulse stimulation at 13 OHM,
150 .mu.F and 50V on glans penis in the presence of an additional 2
mg PGE1 on glans increased intracavernosal pressure from 15 mm Hg
to 22 mm Hg. Response duration was 45 seconds.
Pulse stimulation alone at 13 OHM, 150 .mu.F and 50V on penile
shaft did not affect arterial blood pressure on intracavernosal
pressure. PGE1 (5 mg/20 .mu.l) alone on penile shaft did not affect
arterial or intracavernosal pressure. PGE1 (5 mg/20 .mu.l) on
penile shaft and pulse stimulation on penile shaft at 13 OHM, 150
.mu.F and 50V did not affect arterial or intracavernosal pressure.
A second pulse stimulation at 13 OHM, 400 .mu.F and 60V on penile
shaft in the presence of an additional 5 mg PGE1 on penile shaft
did not affect arterial or intracavernosal pressure. A third pulse
stimulation at 13 OHM, 400 .mu.F and 60V in the presence of an
additional 5 mg PGE1 on the penile shaft did not affect arterial or
intracavernosal pressure.
PGE1 (10 mg/20 .mu.l) on glans penis and penile shaft and pulse
stimulation on glans penis and penile shaft at 13 OHM, 400 .mu.F
and 60V did not affect arterial pressure while causing a remarkable
increase in intracavernosal pressure. With this concentration of
PGE1 and stimulation on the glans and shaft, intracavernosal
pressure increased from 17 mm Hg to 48 mm Hg, resulting in a full
erection (FIG. 4A). After 22 minutes there was a spontaneous
detumescence. A second pulse stimulation at 13 OHM, 400 .mu.F and
60 V on the glans and shaft in the presence of an additional 10 mg
PGE1 on the glans and shaft caused an increase in intracavernosal
pressure from 17 mm Hg to 48 mm Hg, resulting in full penile
erection lasting for 15 minutes (FIG. 4B).
EXAMPLE II
This example shows that topical application of PGE1 or trimix
(papavarine, phentolamine and PGE1) on the penile glans, shaft or
both followed by application of a pulsed electric field induced
penile erection in rabbits.
New Zealand White rabbits (n=6) weighing between 3-3.5 kg were
studied for studies the effect of topical PGE1 crystals, topical
trimix and pulsed electrical field stimulation on penile erection.
The concentration of PGE1 for each topical application was 10
mg/100 .mu.l. The concentration of trimix for each topical
application was 10 mg papavarine+0.5 mg phentolamine+0.2 mg PGE1 in
100 .mu.l.
Animals were anesthetized with intramuscular injection of ketamine
(35 mg/KG) and xylazine (5 mg/kg) and maintained with 0.2 ml
intravenous bolus injections of pentobarbital (25 mg/ml) as needed.
A 25 gauge angiocatheter was placed into the ear vein for
continuous administration of physiologic saline solution. A 20
gauge angiocatheter was placed into the carotid artery and
connected to a transducer for online measurement of systemic
arterial pressure. A 23 gauge minicatheter was placed
intracavernosally and connected to a transducer for measurement of
penile intracavernosal pressure. A meander electrode (1 mm
electrode width and 0.2 mm gap between two electrodes) was modified
in open condom shape and placed around penile shaft and glans and
connected to a BTX ECM600 pulse generator. Systemic arterial
pressure and intracavernosal pressure (ICP) were continuously
recorded before during and after topical application of PGE1 or
trimix and electropulsing using an Astromed chart recorder.
Intracavernosal pressure changes were normalized for arterial
pressure and are presented as the percentage (%) of mean arterial
pressure (FIG. 7). Erectile potency of each animal was confirmed by
intracavernosal trimix injection at the end of the study.
One set of 6 electrical pulses without topical application of
vasodilators on penile shaft and glans did not affect ICP. Six
pulses with topical PGE1 alone also did not affect ICP.
PGE1 or trimix (100 .mu.l) was applied on the penile shaft, glans
and on the electrode followed by pulsed electrical field
stimulation. Three sets of six pulses at 13 OHM, 400 .mu.F, 50-60 V
and 3 ms were applied and their effects on systemic and
intracavernosal pressure were continuously recorded. The meantime
of each set of six pulses was 1 minute. Stimulation with three sets
of six pulses was repeated three times. If the animal failed to
show erectile activity, additional PGE1 or trimix was applied on
the glans and shaft and on the electrode and electric stimulation
was repeated. This was continued until erectile activity was
observed.
Effect of Topical PGE1 and Pulse Electrical Field Stimulation on
Penile Erection
Of the three animals studied, one animal achieved full penile
erection, one animal developed partial erection and one animal
showed only minor erectile activity. The following specific changes
in intracavernosal pressure and systemic arterial pressure were
noted during the studies:
PGE1 #1. Baseline systolic and diastolic arterial pressure was 111
and 84 mm Hg respectively. Baseline intracavernosal pressure was
30% of arterial pressure (PGE #1, FIG. 7). After application of
PGE1 and 6 pulses at 13 OHM, 400 .mu.F and 60V, intracavernosal
pressure was 26% of arterial pressure. After the second and third
sets of 6 pulses intracavernosal pressure decreased to 24% and 22%
of arterial pressure respectively. Additional PGE1 was applied and
stimulation was repeated. Intracavernosal pressure after the first,
second and third set of 6 pulses was 22%, 19% and 16% of arterial
pressure respectively. Additional PGE1 was applied. Since
stimulation at 13 OHM, 400 .mu.F and 60 V caused decrease of ICP,
the remaining stimulations were performed at 13 OHM, 400 .mu.F and
50 V. Electric stimulation with these parameters produced better
erectile activity causing a gradual increase in intracavernosal
pressure. Intracavernosal pressure after the first, second and
third set of 6 pulses was 27%, 24% and 24% of arterial pressure
respectively. Additional PGE1 was applied and pulsing was repeated
at 13 OHM, 400 .mu.F and 50 V. The first set of 6 pulses caused an
increase in intracavernosal pressure to 58% of arterial pressure.
The second set of 6 pulses caused further increase in
intracavernosal pressure to 95% of systemic arterial pressure (PGE
#1, FIG. 7). This animal developed full prolonged penile erection
(FIG. 5A) and therefore did not require intracavernosal trimix
injection to confirm erectile potency. At this time, the systolic
and diastolic pressures were 120 mm Hg and 87 mm Hg
respectively.
PGE1 #2. Baseline systolic and diastolic arterial pressures were 90
and 60 mm Hg respectively. Baseline intracavernosal pressure was
35% of arterial pressure (PGE #2, FIG. 7). After application of
PGE1 and 6 pulses at 13 OHM, 400 .mu.F and 50 V, the
intracavernosal pressure was 47% of arterial pressure. After the
second and third set of 6 pulses, intracavernosal pressure was 43%
and 44% of arterial pressure respectively. Additional PGE1 was
applied and pulsing was repeated. Intracavernosal pressure after
the first, second and third set of 6 pulses was 36%, 42% and 40% of
arterial pressure respectively. Another three sets of 6 pulses was
applied. Intracavernosal pressure after the first, second and third
set of 6 pulses was 48%, 44% and 41% of arterial pressure
respectively. Another set of pulses was applied. Intracavernosal
pressure after first, second and third set of 6 pulses was 45%, 45%
and 44% of arterial pressure respectively. Additional PGE1 was
applied and stimulation was repeated. Intracavernosal pressure
after first, second and third set of 6 pulses was 43%, 47% and 47%
of arterial pressure respectively. Additional PGE1 was applied and
pulsing repeated. Intracavernosal pressure was first, second and
third set of 6 pulses gradually increased to 57%, 58% and 60% of
men arterial pressure respectively. Two additional sets of 6 pulses
were applied. After the first set of pulses, intracavernosal
pressure increased to 63% of arterial pressure. After the second
set of stimulation, intracavernosal pressure increased to 65% of
mean arterial pressure (PGE #2, FIG. 7). At this time, the animal
was hypotensive (systolic and diastolic arterial pressure were 72
and 57 mm Hg respectively). This animal developed a partial penile
erection (FIG. 5B). Intracavernosal trimix injection caused full
penile erection.
PGE1 #3. Baseline systolic and diastolic arterial pressures were
102 and 66 mm Hg respectively. Baseline intracavernosal pressure
was 35% of arterial pressure (PGE #3, FIG. 7). After application of
PGE1 and 6 pulses at 13 OHM, 400 .mu.F and 50 V, intracavernosal
pressure was 39% of arterial pressure. After the second and third
set of 6 pulses, intracavernosal pressure was 35% and 30% of
arterial pressure respectively. Additional PGE1 was applied and
pulsing was repeated. Intracavernosal pressure after the first,
second and third set of 6 pulses was 35%, 36% and 39% of arterial
pressure respectively. Additional PGE1 was applied and three sets
of 6 pulses were repeated. Intracavernosal pressure after the
first, second and third set of 6 pulses was 45%, 45% and 47% of
arterial pressure respectively. Another set of pulses was applied.
Intracavernosal pressure after the first, second and third set of 6
pulses was 47%, 48% and 48% of arterial pressure respectively.
Additional PGE1 was applied and pulsing repeated. Intracavernosal
pressure after the first, second and third set of 6 pulses was 43%,
41% and 41% of mean arterial pressure respectively. Since a large
amount of PGE1 was already applied on the glans and shaft,
additional PGE1 was avoided while stimulation was continued. Twelve
additional sets of 6 pulses were applied. In the final stimulation,
intracavernosal pressure after the first, second and third pulses
was 46%, 50% and 50% of arterial pressure respectively (PGE #3,
FIG. 7). At this time, the systolic and diastolic pressure was 98
mm Hg and 63 mm Hg respectively. This animal showed some erectile
activity but the quality of erection was poor (FIG. 5C).
Intracavernosal trimix injection caused full penile erection.
Effects of Topical Trimix and Pulse Electrical Field Stimulation on
Penile Erection
Of the three animals studied, one animal achieved full penile
erection while the other two animals showed partial erection. The
following specific changes in intracavernosal pressure and systemic
arterial pressure were noted during the experiments:
Trimix #1. Baseline systolic and diastolic arterial pressure was
105 and 84 mm Hg respectively. Baseline intracavernosal pressure
was 34% of arterial pressure (Trimix #1, FIG. 7). After one set of
6 pulses alone (without trimix) at 13 OHM, 400 .mu.F and 50 V,
intracavernosal pressure was 33% of arterial pressure. After the
second and third set of 6 pulses, intracavernosal pressure was 36%
and 36% of arterial pressure respectively. After application of
trimix, intracavernosal pressure after the first, second and third
set of 6 pulses was 35%, 36% and 38% of arterial pressure
respectively. Additional trimix was applied and pulsing was
repeated. Intracavernosal pressure after the first, second and
third set of 6 pulses was 40%, 40% and 42% of arterial pressure
respectively. Additional trimix was applied and pulsing was
repeated. After the first, second and third set of 6 pulses,
intracavernosal pressure was 52%, 55% and 67% of arterial pressure
respectively. Another three set of 6 pulses was applied.
Intracavernosal pressure after the first, second and third pulses
was 70%, 74% and 90% of arterial pressure respectively (Trimix #1,
FIG. 7). At this time, systolic and diastolic pressures were 107 mm
Hg and 82 mm Hg respectively. This animal developed a full
prolonged penile erection (FIG. 6A). Trimix #2. Baseline systolic
and diastolic arterial pressure was 96 and 78 mm Hg respectively.
Baseline intracavernosal pressure was 24% of arterial pressure
(Trimix #2, FIG. 7). One set of 6 pulses alone (without trimix) at
13 OHM, 400 .mu.F and 50 V did not affect intracavernosal pressure.
After application of trimix and 6 pulses at 13 OHM, 400 .mu.F and
50 V, intracavernosal pressure was 37% of arterial pressure. After
the second and third set of 6 pulses, intracavernosal pressure was
41% and 40% of arterial pressure respectively. Another three sets
of 6 pulses was intracavernosal pressure 39%, 42% and 43% of
arterial pressure respectively. Additional trimix was applied and
pulsing was repeated. Intracavernosal pressure after the first,
second and third set of 6 pulses was 47%, 52% and 49% of arterial
pressure respectively. Another three sets of 6 pulses were applied.
Intracavernosal pressure after the first, second and third set of 6
pulses was 49%, 55% and 55% of arterial pressure respectively.
Another three sets of 6 pulses were applied. Intracavernosal
pressure after the first, second and third set of 6 pulses was 55%,
55% and 64% of arterial pressure respectively. Additional three
sets of 6 pulses were applied. Intracavernosal pressure after the
first, second and third pulses was 53%, 53% and 59% of arterial
pressure respectively. Additional trimix was applied and pulsing
repeated. Intracavernosal pressure after the first, second and
third set of 6 pulses was 63%, 65% and 69% of arterial pressure.
Another three sets of 6 pulses were applied. Intracavernosal
pressure after the first, second and third set of 6 pulses was 64%,
65% and 67% of arterial pressure respectively (Trimix #2, FIG. 7).
At this time, systolic and diastolic arterial pressure were 90 and
57 mm Hg respectively. This animal developed a partial penile
erection (FIG. 6B). Intracavernosal trimix injection caused full
penile erection.
Trimix #3. Baseline systolic and diastolic arterial pressure was 93
and 69 mm Hg respectively. Baseline intracavernosal pressure was
28% of systemic arterial pressure (Trimix #3, FIG. 7). One set of 6
pulses at 13 OHM, 400 .mu.F and 50 V did not affect intracavernosal
pressure. After application of trimix and 6 pulses at 13 OHM, 400
.mu.F and 50 V, intracavernosal pressure was 33% of arterial
pressure. After the second and third set of 6 pulses,
intracavernosal pressure was 34% and 33% of arterial pressure
respectively. Another three sets of 6 pulses were applied.
Intracavernosal pressure after the first, second and third set of 6
pulses was 45%, 43% and 43% of arterial pressure respectively.
Another three sets of 6 pulses were applied. Intracavernosal
pressure after the first, second and third set of 6 pulses was 43%,
43% and 43% of arterial pressure respectively. Additional trimix
was applied and three sets of 6 pulses were repeated.
Intracavernosal pressure after the first, second and third set of 6
pulses was 63%, 56% and 62% of arterial pressure respectively.
Another three sets of 6 pulses were applied. Intracavernosal
pressure after the first, second and third set of 6 pulses was 65%,
67% and 71% of arterial pressure respectively (Trimix #3, FIG. 7).
Additional pulsing did not further increase intracavernosal
pressure. At this time, the systolic and diastolic pressure was 93
mm Hg and 60 mm Hg respectively. This animal developed a partial
short lived erection (FIG. 6C). Intracavernosal trimix injection
caused full penile erection.
To summarize, in the three animals with topical PGE1 application,
pulsed electric field stimulation caused full penile erection in
the first animal, partial erection in the second animal and
relatively poor but detectable erectile activity in the third
animal. In the three animals with topical trimix application,
pulsed electric field stimulation caused full penile erection in
the first animal while causing partial erection in the second and
third animals. Pulsed electrical stimulation with topical trimix
appears to be slightly more effective in producing erectile
activity compared to pulsed electrical stimulation with topical
PGE1.
These studies show that topical application of vasodilators in
conjunction with electric pulsing induces erectile activity in the
rabbit. Although the effect of electric pulsing in producing
erectile activity varied among the animals, at least some amount of
erectile activity was produced up to a full prolonged erection in
every animal.
EXAMPLE III
This example shows that topical application of PGE1 or trimix
(papavarine, phentolamine and PGE1) on the penile glans or shaft
without application of electric pulsing fails to induce penile
erection in rabbits. This example also shows that applying electric
pulsing alone (without application of vasodilator) fails to induce
penile erection in rabbits.
New Zealand White rabbits (n=6) weighing between 3-3.5 kg were
divided into three groups for studies of the effect of topical PGE1
crystals on erectile function (n=2); for studies of the effect of
topical trimix on erectile function (n=2); and for studies of the
effect of electric pulsing on penile erection. The concentration of
PGE1 for each topical application was 10 mg/100 1 and the
concentration oftrimix for each topical application comprised 10 mg
papavarine+0.5 mg phentolamine+0.2 mg PGE1 in 100 .mu.l.
Animals were anesthetized as before. A 25 gauge angiocatheter was
placed into the ear vein for continuous administration of
physiologic saline solution. A 20 gauge angiocatheter was placed
into the carotid artery and connected to a transducer for on-line
measurement of systemic arterial pressure. A 23 gauge minicatheter
was placed intracavernosally and connected to a transducer for
measurement of intracavernosal pressure. A meander electrode was
placed around the penile shaft and glans and connected to a BTX
ECM600 pulse electrical field generator. Arterial and
intracavernosal pressures were continuously recorded on an Astromed
chart recorder throughout the procedure. Intracavernosal pressure
changes were normalized for arterial pressure and are presented as
the percentage (%) of Systemic Arterial Pressure (FIG. 8). Erectile
potency of rabbits was confirmed by intracavernosal trimix
injection at the end of the studies.
Studies with Topical PGE1 and with Topical Trimix without Electric
Pulse Stimulation
Baseline systemic arterial pressure and intracavernosal pressure
were recorded. PGE1 (10 mg/100 .mu.l) or trimix (10 mg
papaverine+0.5 mg phentolamine+0.2 mg PGE1 in 100 .mu.l) was
applied to the glans, penile shaft and electrode. After three
minutes, a second dose of PGE1 or trimix was applied. Topical
application of PGE1 or trimix on penile glans, shaft and electrode
was repeated up to four doses in three minute intervals. After
topical application, systemic arterial and intracavernosal
pressures were recorded for an additional ten minutes.
In two animals, topical administration of four doses of PGE1 on the
glans, penile shaft and electrode without pulsed electrical field
stimulation did not affect systemic and intracavernosal pressures
(PGE1 #1 and #2, FIG. 8). Baseline intracavernosal pressures before
administration of PGE1 in the two animals were 25% and 28% of
systemic arterial pressure. After the fourth dose application of
PGE1, systemic and intracavernosal pressures in the two animals
were 27% and 30% of systemic arterial pressure. These differences
after topical PGE1 were not statistically significant compared to
those recorded before PGE1 administration. Intracavernosal
pressures after intracavernosal trimix injection of the two
animals, however, reached 92% and 95% of systemic arterial
pressure, confirming erectile potency.
In two animals, topical administration of four doses of trimix on
the glans, penile shaft and electrode without pulsed electrical
field stimulation did not affect systemic and intracavernosal
pressures (Trimix #1 and #2, FIG. 8). Baseline intracavernosal
pressures before administration of trimix in the two animals were
30% and 33% of systemic arterial pressure. After the fourth dose of
topical trimix, intracavernosal pressures in the two animals were
25% and 35% of systemic arterial pressure. These differences after
topical trimix were not statistically significant compared to those
recorded before trimix administration. Intracavernosal pressures
after intracavernosal trimix injection of in the two animals,
however, reached 90% and 97% of systemic arterial pressure,
confirming erectile potency.
Studies with Electric Pulse Stimulation without Topical
Vasodilators
Baseline systemic arterial pressure and intracavernosal pressure
were recorded. After application of 100 .mu.l buffer on glans,
penile shaft and electrode, one set of six pulses (50 V, 13 OHM and
400 .mu.F) was applied. After this the second and third set 6
pulses were applied in one minute intervals. After three sets of
six pulses were applied, additional buffer (100 .mu.l) was applied
on the glans, penile shaft and electrode. The three sets of six
pulses were repeated while adding buffer after every three sets of
six pulses. This was repeated until a total of 20 sets of electric
pulsing. After the 20th set of electric pulsing, systemic arterial
and intracavernosal pressures were measured for an additional 10
minutes.
Without topical administration of vasodilators, 20 sets of six
electric pulses applied to the glans and penile shaft of two
animals did not affect systemic and intracavernosal pressures (EP#1
and #2, FIG. 8). Baseline intracavernosal pressures before electric
pulsing in the two animals were 18% and 34% of systemic arterial
pressure. After the 20th set of electric pulsing intracavernosal
pressures were statistically similar to those recorded before
electrical field stimulation. After the 20th set of electric
pulsing intracavernosal pressures in the two animals were 27% and
38% of systemic arterial pressure. These differences after electric
pulsing were not statistically significant compared to those
recorded before stimulation. Intracavernosal pressures after
intracavernosal administration of trimix in the two animals,
however, reached to 91% and 95% of systemic arterial pressure
confirming erectile potency.
These studies show that transdermal introduction of a topical
application of vasodilators (e.g., PGE1 and trimix) require
applying an electric pulse for inducing erectile activity. These
studies also show that an electric pulse without topical PGE1 or
trimix is not capable of producing erectile activity in the
rabbit.
EXAMPLE IV
This example shows that PGE1, used for self-injection therapy in
erectile dysfunction, can be transdermally introduced into human
skin in vitro and human penile skin by electric pulsing alone, or
in combination with iontophoresis, thereby providing a non invasive
mode of drug delivery.
Materials
Prostaglandin E1 (PGE1) and tritium-labeled Prostaglandin E1
(.sup.3 H-PGE1) was obtained from Sigma (St. Louis, Mo.). Labeled
drug was received in 7:3 ethanol:water mixture. The drug was
protected from light during all studies, which were done in
triplicate. Scintillation cocktail (ULTIMA-GOLD.TM.) and
SOLVABLE.TM. tissue and gel solubilizer were obtained from Packard
(Meriden, CT). Human cadaver skin and penile skin obtained from
skin banks had been frozen within 12 hours of death and supplied as
full thickness skin, unless otherwise specified. Once received, the
skin was stored at -80.degree. C. and then thawed just before use.
Full thickness or dermatomed human cadaver skin or penile skin was
used. Buffer components and other chemicals were obtained from
Fisher Scientific (Pittsburgh, Pa.); silver-silver chloride
electrodes were purchased from In Vivo Metric (Healdsburg, Calif.);
and meander electrodes were from Genetronics, Inc. (San Diego,
Calif.).
Solution Studies
For these studies, the drug was in solution though the final
formulation may have been a suspension due to the addition of latex
or dextran particles. PGE1 (5.6 .mu.g) was dissolved in
ethanol:water (7:3) and spiked with .sup.3 H-PGE1. A few
microliters of this solution was placed on full thickness human
skin and covered with a meander electrode, which consists of an
interweaving array of metal fingers coated on a thin plastic film.
Pulses were applied via these metal fingers on the meander
electrode creating an electric field that breaks down the stratum
corneum of the skin. Slight pressure was applied on the electrode
during pulsing either by clamping the whole set-up on a table top
or by clamping the set-up on the upper half of a Franz cell.
Further details on this pressure-mediated "electroincorporation"
technique can be found in Hofmann et al., Bioelectrochem. Bioenerg.
38 (1995) 209-222 and Zhang et al., Bioelectrochem. Bioenerg. 42
(1997) 283-292. Following table top pulsing, the skin was
transferred in some cases to glass diffusion cells. In this case,
the donor and receptor solutions were filled with 4 ml of HEPES
buffer and iontophoresis was applied in some cases using
silver/silver chloride electrodes.
Suspension Studies
For these studies, the drug was in suspension. In a typical
suspension study, prostaglandin (PGE1 and .sup.3 H-PGE1) was
dissolved in ethanol and then ethanol was removed by drying under
nitrogen. This procedure helped to molecularly disperse PGE1 and
.sup.3 H-PGE1 together. The dried powder was then resuspended in 10
mM phosphate buffer so that a suitable concentration of
prostaglandin in a small volume (typically, few .mu.l) is achieved.
The analysis was then done by liquid scintillation counting. In
cases where immunoassay was used, .sup.3 H-PGE1 was not used but
PGE1 was still recrystallized from ethanol so that a similar
particle size distribution is obtained. Particles of the
recrystallized suspension were mostly needle shaped, with a width
of about 1 micron and a length of about 5 microns. Some spherical
particles of 1-2 micron size were also seen. The original particle
size of PGE1 received from supplier was in the range of 5-20
microns, seen as crystalline particles, though some particles as
large as 45 micron were also seen. Recrystallization seems to have
resulted in a more uniform particle size distribution. When the
Franz cell set-up was used, the skin was cut into 1 inch square
pieces (pulsing area 0.64 cm.sup.2) for electroporation
experiments, and appropriate controls were treated with PGE1 but
not pulsed. The skin was placed on Franz cell, the drug suspension
was added, meander electrode with a well created by a double-sided
tape was placed on this solution, a parafilm was placed on meander
electrode and then a metal disc was placed on the top before
clamping the donor chamber for intimate contact. More consistent
results were obtained when the suspension was contained in this
well created on the meander electrode using double sided tape an
the whole experiment was done on the Franz cell setup. In the
absence of this well, the solution under meander electrode could be
squeezed out by the applied pressure.
The experimental group pieces of skin were typically pulsed with 6
pulses of 100 V or 120V and 10-20 ms duration. In some cases, 6
additional pulses were applied after a one minute rest. The skin
was then left on the set-up for 15 minutes, at which time a
receiver sample was taken and the skin was removed. In some
studies, additional sampling was done to study the slow release of
drug from the skin. Following the study, the skin was cleaned with
three cotton swabs wetted with buffer (with dry tips in between) to
wipe out the treated side, cut into several pieces, sometimes
followed by one tape stripping. The blade used for cutting and the
petridish in which the skin was cut were washed with the skin
solubilizer and the skin and washings were transferred to
solubilizer and digested at 75.degree. C. for 2 days. For
experiments using ELISA assay, the skin was not dissolved in
solubilizer but rather extracted by the procedure described
hereinbelow.
Skin Extraction & Immunoassay
Skin samples were weighed and then cut into small pieces. The skin
was then placed into a beaker with 10 ml PBS buffer, homogenized
using a homogenizer (OMNI 5100) at moderate speed and it was passed
through samples for about 4-5 minutes. The homogenate was acidified
with 1 N HCI to a pH of 3.5 to 4.0, and transferred to a
siliconized glass tube; 2 ml of phosphate buffer was used to
transfer the residue from the beaker. The skin homogenate was then
extracted with 20 ml of ethyl acetate and 4500 dpm of .sup.3 H-PGD2
was added for measurement of extraction efficiency.
Sample was vortexed for 10 mins and centrifuge at 3000.times.g for
15 mins. The top layer was drawn off into a siliconized tube and
extracted with another 20 ml ethyl acetate, followed by vortexing
and centrifugation, as before. The ethyl acetate fractions were
pooled, dried under nitrogen and resuspended in 3 ml of ethyl
acetate; aliquots were removed for determination of extraction
efficiency and prostaglandin analysis. PGE1 content was determined
using an enzyme immunoassay (EIA) kit (Assay Design Inc., MI).
Samples were aliquoted as follows: 500 .mu.l (suspended in EIA
buffer) for EIA, 1000 .mu.l (suspended in 10 mM Phosphate buffer)
for measurement of recovery; the rest of the 1.5 ml sample was
stored in ethyl acetate at -20.degree. C. The EIA aliquot was dried
and suspended in 500 .mu.l of assay buffer provided with the kit
and the assay was performed according to kit instructions. The
optical density of the samples was read using a BioRad microplate
reader model 4500 and sample concentrations were calculated using
microplate reader software version 2.03 by BioRad and Microsoft
Excel, using dilution and extraction efficiency into
consideration.
Solution Formulation
A solution study with iontophoresis in a diffusion cell was first
carried out to establish the electrode polarity for optimal
delivery. It was observed that 30 minutes of iontophoresis could
increase the permeation of PGE1 across skin several fold over
passive diffusion, with the highest delivery under cathode (FIG.
9). The corresponding amount in the skin at the end of the study
was 1.21.+-.0.76 .mu.g/cm.sup.2 (passive), 0.69.+-.0.14
.mu.g/cm.sup.2 (cathode), and 0.77.+-.0.1 .mu.g/cm.sup.2 (anode).
The use of pulsing (6 pulses of 100 V, 10 ms each) prior to
iontophoresis increased the amount delivered into skin. This was
true irrespective of whether pulses were applied by meander or wire
(cathode) electrode. The amount with meander electrodes was
2.42.+-.1.09 .mu.g/cm.sup.2 in skin and 2.77.+-.1.0 .mu.g/cm.sup.2
in receptor, while with wire electrodes, the amount in skin was
4.23.+-.2.09 .mu.g/cm.sup.2 and in receptor was 1.02.+-.0.08
.mu.g/cm.sup.2.
Pulsing Solution Formation with Particles
PGE1 (5.6 .mu.g) was dissolved in 7:3 ethanol:water (20 .mu.l) and
either latex (2.5%) or dextran (5%) particles were added. The
formulation was placed on full-thickness human cadaver skin, and
three pulses (120V, 10 ms each) were applied by meander electrodes.
Following electroporation, the skin was mounted on transdermal
glass diffusion cells. The exposed area of the skin to the receiver
compartment was the same 0.64 cm.sup.2 to which the drug solution
was applied. The receptor compartment contained 4 ml of HEPES
buffer. The amount of prostaglandin coming out from skin into the
receptor compartment was measured as a function of time (FIG. 10).
Control experiments were also done in which all variables were same
but no pulse was applied. Following the study, the skin was
removed, incubated with a tissue solubilizer and then analyzed to
quantitate the amount of PGE1 remaining in the skin. Based on the
cumulative perneation and the amount that remains in the skin at
the end of the study, the amount of PGE1 in skin just after pulsing
was 0.46.+-.0.03 .mu.g/cm.sup.2 for the latex particle study and
0.56.+-.0.09 .mu.g/cm.sup.2 or the dextran particle study. Thus, it
appears that of the amount delivered into skin by pulsing, about
80% is released into receptor over a period of 5 days. This was
followed by a higher concentration study, in which 200 .mu.g PGE1
was placed on the skin and pulsed with latex particles. The
delivery was again higher in presence of pulsing.
The effect of increasing concentration of prostaglandin was
investigated, applying 5, 20, 100 and 200 .mu.g of PGE1 to full
thickness skin, in a 8 .mu.l volume. Six pulses (120V, 20 ms each)
were applied with a 5-minute post pulse application of pressure.
For the control group without dextran, everything was the same
except pulses were not applied. Results indicate that a higher
amount of PGE1 was delivered into the skin as the PGE1
concentration increased.
Electroporation of PGE1 Suspension
In a study with full thickness skin (average thickness 0.73 mm), a
300 .mu.g/6 .mu.l PGE1 suspension was applied with a meander
electrode by six pulses (100 V, 20 ms) followed by another six
pulses after a one minute rest. The amount of PGE1 in pulsed skin
was found to be 3.08.+-.0.68 .mu.g/cm.sup.2, while in control skin
was 1.62.+-.0.47 .mu.g/cm.sup.2. No PGE1 was detected in receiver
at the end of the study (15 minutes after pulsing), suggesting that
the drug was not driven across the skin. The p-value on a two-tail
test is 0.023. Thus, the data was still statistically significant
in the 0.05 level.
When this protocol was used on dermatomed skin and sampling time
was increased to 24 hours, PGE1 was found to permeate into the
receiver indicating traversal of the skin. The cumulative amount of
PGE1 permeated into receiver as a function of time following
pulsing is shown in FIG. 11. The total amount permeated into the
receiver in 24 hours was 6.43.+-.2.17 .mu.g for the pulsing group
and 2.0.+-.0.57 .mu.g for the unpulsed control group. The amount of
PGE1 in pulsed skin at 24 hours was 14.44.+-.4.29 .mu.g, while in
control skin was 5.68.+-.3.25 .mu.g. The p-value on a two-tail test
is 0.048. Thus, the data is statistically significant at the 0.1
level. If this data is adjusted for the amount permeated into
receiver over 24 hours, then the amount of PGE1 delivered into skin
following pulsing is 20.87 .mu.g for pulsed group and 7.68 .mu.g
for control group. The amount in pulsed skin is about 6-7 times
higher than an earlier study in which sampling was done in 15
minutes using full-thickness skin. In earlier studies (15 minutes
sampling), no PGE1 was detected in receiver at the end of the
study, suggesting that the drug slowly diffuses out of the skin
over a period of several hours.
Another suspension study analyzed the data by immunoassay. A
concentration of 100 .mu.g/8 .mu.l of prostaglandin in distilled
water was prepared, and the resulting product was observed to be a
suspension. A volume of 8 .mu.l of this suspension was placed on
skin for pulsing. The skin was placed on a metal plate and pulse
was applied using meander electrodes under a lead weight (435 g).
Pulsing studies were conducted on full-thickness human cadaver
skin, using six pulses (120 V, 20 ms each). Control studies were
then done in which the drug suspension was placed on skin and
pressure applied for 2 minutes (to simulate the time it takes to
give six pulses) but no pulse was applied. These six pieces of skin
and one piece of untreated skin were then analyzed by enzyme
immunoassay. The skin was not digested by the tissue solubilizer as
the strong base used in these solubilizers may have deleterious
effect on the stability of prostaglandins. This was not a
consideration in earlier experiments as only the radioactivity
(cpm) had to be quantitated following the experiment; the total cpm
would not be affected even if prostaglandin degrades after the
pulsing has been performed. The results show that the pulsed skin
(2.19.+-.1.38 .mu.g/cm.sup.2) had a higher amount of PGE1 than the
unpulsed control skin (1.19.+-.0.31 .mu.g/cm.sup.2). The efficiency
of delivery has higher than that achieved by earlier studies with
PGE1 solution or PGE1 dextran/latex particles.
Release of Drug from Pulsed Skin
A concentration of 20 .mu.g/16 .mu.l of prostaglandin in 7:3
ethanol:water was spiked with .sup.3 H-PGE, and dextran particles
(5% w/v) were added to this solution. A volume of 16 .mu.l of this
solution was placed on full-thickness human cadaver skin (six
pulses, 120 V, 20 ms) were applied by meander electrodes. Following
pulsing, the skin was mounted on diffusion cells and samples were
taken at periodic intervals (FIG. 12). The drug was allowed to be
released from pulsed skin either by itself (pulses only) or by use
of iontophoresis (20 minutes) to drive out the drug reservoir
(pulses followed by iontophoresis). A control study also was done
in which all variables were the same but no pulse or iontophoresis
was applied. As shown in FIG. 12, the unpulsed control had much
lower amounts as compared to pulsed skin, with the most drug being
released by iontophoresis of pulsed skin. This is most likely
because iontophoresis provided the driving force to push the drug
reservoir out from the skin.
Studies with Penile Skin
A therapeutic dose could also be delivered within a short period of
time. To accomplish this, however, the concentration of PGE1 had to
be increased. To establish that aforementioned studies are
predictive of the end use of this technology (e.g., treating
erectile dysfunction or inducing, enhancing or maintaining erectile
function), penile skin was examined. A concentration of 1.0 mg PGE1
suspension in 6.0 .mu.l was used in this case. Full thickness
(average thickness 0.38 mm) human cadaver penile skin was used and
pulsed on the Franz cell setup as before. Six pulses (10 ms each)
of 100 V each were applied. The amount of PGE1 in pulsed skin and
in control skin was 19.88.+-.0.93 .mu.g and 15.76.+-.0.05 .mu.g,
respectively. The p-value on a two-tail test is 0.017. Thus, the
data is statistically significant at the 0.05 level. The high
unpulsed control value may be due to the inability to wash the skin
surface properly prior to analysis or driving particles into the
skin by pressure in the absence of an electric pulse.
This study was repeated using enzyme immunoassay and PGE1 directly
from the vial. A concentration of 1 mg/6 .mu.l of prostaglandin in
10 mM phosphate buffer was prepared directly using the PGE1
material from Sigma, without any ethanol crystallization. The skin
was then homogenized and extracted as before. The amount of PGE1 in
pulsed skin and in control skin was 12.02.+-.6.42 .mu.g and
15.09.+-.9.86 .mu.g, respectively. The p-value on a two-tail test
is 0.67. Thus, the difference between pulsed and unpulsed control
skin is not statistically significant. Since earlier studies gave a
statistically significant difference, it appears that
recrystallization from ethanol, which produces a more homogeneous
drug distribution for the donor suspension, increases transdermal
delivery. PGE1 directly from the vial may have a nonuniform
particle size distribution, in which case the dose for each
replicate will vary even though the same volume is used.
Alternatively, the variation could result from skin homogenization
not being very effective in releasing all the drug from the
microstructure of the skin into solution. In earlier studies with
PGE/.sup.3 H-PGE, the skin is dissolved which will result in
complete release of the drug into solution. In any case, enzyme
immunoassay data is still in the therapeutic range, which indicates
that the end point therapeutic use is feasible. As the data is in
therapeutic range with this assay, this suggests that significant
degradation to the point of losing most of the drug is not
occurring. When pulsed with six 100 V (20 ms) pulses are applied
with a meander electrode, the penile skin was observed to develop
slight burn marks, suggesting that penile skin is more sensitive
and has lower resistance than skin from other sites; thus, pulse
length has to be low when using meander electrodes that are in
direct contact with penile skin.
The variability between pulsed and unpulsed skin may have resulted
from even one particle embedding in the skin in unpulsed control,
which would significantly increase the amount of PGE1 calculated in
the skin. A further confounding effect could have been due to the
use of ethanol, which is a known penetration enhancer for
transdermal delivery. However, it is not clear if ethanol could
have exerted its effect in the short time it was on the skin before
skin was digested by tissue solubilizer. Alternatively, inadequate
skin washing could have increased the amount of PGE1 in unpulsed
control skin.
To summarize, these studies show that PGE1 in solution can be
delivered into human skin by electric pulses. Further enhancement
is achieved when inert particles are mixed with the formulation and
delivered with a meander electrode (i.e. electropulsing in
combination with iontophoresis). If a drug suspension is used, then
relatively large amounts can be delivered into human skin by high
voltage pulses. Trasndermal drug delivery via electrical pulsing is
potentially useful in patients who do not respond to other
treatments for erectile dysfunction such as VIAGRA.TM., or cannot
tolerate the side effects.
EXAMPLE V
This example shows that electropulsing under conditions sufficient
to transdermally introduce compositions into the rabbit penis is
well tolerated by human subjects.
Genetronics, Inc. has sponsored a Phase I feasibility study of
human sensation tolerance on the method and the electrical
apparatus (no drug was involved in this study). The institutional
IRB approval and Patient Consent Form were generated prior to the
study. The pain level of electrical therapy was assessed in 20
patients that had previously undergone either cavernosal injection
therapy or transurethra insertion therapy, 10 patients per group.
Sterile PBS was used as a placebo for all pulsing sensation tests.
The setup of pulse applicator (shown in FIG. 3, where the cuff
provided controlled pressure) ensured good contact between the
electrodes and the skin (midshaft and partial glans).
Patients were subjected to a single pulse of 50 to 80 volts in 10
volt increments delivered for 3 msec. The patients were asked to
rate the pulse sensation on a scale of 0, no pain, to 10,
excruciating. The results of this study shown in FIG. 13 and are
summarized as follows: (1) All patients passed single pulsation
tests (50 V-80 V, 3 ms) without rating the sensation excruciating
pain. (2) The pulse sensation was tolerable; from 60 V to 80 V,
77.5% of subjects rated the electropulse from no pain to
discomforting and only 10% rated the sensation from distressing to
horrible. (3) No side effects of pulsing were observed or reported.
It was concluded that the method and apparatus are safe and
acceptable to patients under electrical pulse conditions sufficient
to transdermally introduce a composition into the penis.
While this invention has been described as having certain
embodiments, it is understood that further modifications, uses
and/or adaptations of the invention are possible, and are
encompassed by the invention set forth in the following claims.
* * * * *